N-benzyl-3-phenyl-3-heterocyclyl-propionamide compounds as tachykinin and/or serotonin reuptake inhibitors

ABSTRACT

The present invention relates to heterocyclic derivatives of formula (I)  
                 
wherein 
     R represents halogen, C 1-4  alkyl, cyano, C 1-4  alkoxy, trifluoromethyl or trifluoromethoxy;    R 1  represents a 5 or 6 membered heteroaryl group, in which the 5-membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-membered heteroaryl group contains from 1 to 3 nitrogen atoms, or R 1  represents a 4, 5 or 6 membered heterocyclic group, wherein saids 5 or 6 membered heteroaryl or the 4, 5 or 6 membered heterocyclic group may optionally be substituted by one to three substituents, which may be the same or different, selected from (CH 2 ) p R 6 , wherein p is zero or an integer from 1 to 4 and R 6  is selected from: halogen, 
       C 1-4 alkoxy,    C 1-4 alkyl,    C 3-7 cycloalkyl,    C 1-4  alkyl optionally substituted by halogen, cyano or C 1-4  alkoxy, hydroxy, cyano, nitro, trifluoromethyl, carboxy,    NH(C 1-4  alkyl),    N(C 1-4  alkyl) 2      NH(C 3-7  cycloalkyl),    N(C 1-4  alkyl)(C 3-7  cycloalkyl);    NH(C 1-4 alkylOC 1-4 alkoxy),    OC(O)NR 7 R 8 ,    NR 8 C(O)R 7  or    C(O)NR 7 R 8 ;    
       R 2  represents hydrogen, or C 1-4  alkyl;    R 3  and R 4  independently represent hydrogen, C 1-4  alkyl or R 3  together with    R 4  represents C 3-7  cycloalkyl;    R 5  represents trifluoromethyl, S(O) q C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy, trifluoromethoxy, halogen or cyano;    R 7  and R 8  independently represent hydrogen, C 1-4  alkyl or C 3-7  cycloalkyl; L is a single or a double bond; n is an integer from 1 to 3; m is zero or an integer from 1 to 3; q is zero or an integer from 1 to 2; provided that    a) when L is a double bond, R 1  is not an optionally substituted 5 or 6 membered heteroaryl group, in which the 5-membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-membered heteroaryl group contains from 1 to 3 nitrogen atoms;    b) the group R 1  is linked to the carbon atom shown as * via a carbon atom; and    c) when the heteroatom contained in the group R 1  is substituted, p is not zero; and pharmaceutically acceptable salts and solvates thereof; process for their preparation and their use in the treatment of conditions mediated by tachykinins and/or by selective inhibition of serotonin reuptake transporter protein.

The present invention relates to heterocyclic derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their medical use.

The present invention thus provides compounds of formula (I)

wherein

-   R represents halogen, C₁₋₄ alkyl, cyano, C₁₋₄ alkoxy,    trifluoromethyl or trifluoromethoxy;-   R₁ represents a 5 or 6 membered heteroaryl group, in which the    5-membered heteroaryl group contains at least one heteroatom    selected from oxygen, sulphur or nitrogen and the 6-membered    heteroaryl group contains from 1 to 3 nitrogen atoms, or R₁    represents a 4, 5 or 6 membered heterocyclic group, wherein saids 5    or 6 membered heteroaryl or the 4, 5 or 6 membered heterocyclic    group may optionally be substituted by one to three substituents,    which may be the same or different, selected from (CH₂)_(p)R₆,    wherein p is zero or an integer from 1 to 4 and R₆ is selected from:    -   halogen,    -   C₁₋₄alkoxy,    -   C₁₋₄alkyl,    -   C₃₋₇cycloalkyl,    -   C₁₋₄ alkyl optionally substituted by halogen, cyano or C₁₋₄        alkoxy,    -   hydroxy,    -   cyano,    -   nitro,    -   trifluoromethyl,    -   carboxy,    -   NH(C₁₋₄ alkyl),    -   N(C₁₋₄ alkyl)₂    -   NH(C₃₋₇ cycloalkyl),    -   N(C₁₋₄ alkyl)(C₃₋₇ cycloalkyl);    -   NH(C₁₋₄alkylOC₁₋₄alkoxy),    -   OC(O)NR₇R₈,    -   NR₈C(O)R₇ or    -   C(O)NR₇R₈;-   R₂ represents hydrogen, or C₁₋₄ alkyl;-   R₃ and R₄ independently represent hydrogen, C₁₋₄ alkyl or R₃    together with R₄ represents C₃₋₇ cycloalkyl;-   R₅ represents trifluoromethyl, S(O)_(q)C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄    alkoxy, trifluoromethoxy, halogen or cyano;-   R₇ and R₈ independently represent hydrogen, C₁₋₄ alkyl or C₃₋₇    cycloalkyl;-   L is a single or a double bond;-   n is an integer from 1 to 3;-   m is zero or an integer from 1 to 3;-   q is zero or an integer from 1 to 2;    provided that-   a) when L is a double bond, R₁ is not an optionally substituted 5 or    6 membered heteroaryl group, in which the 5-membered heteroaryl    group contains at least one heteroatom selected from oxygen, sulphur    or nitrogen and the 6-membered heteroaryl group contains from 1 to 3    nitrogen atoms;-   b) the group R₁ is linked to the carbon atom shown as * via a carbon    atom; and-   c) when the heteroatom contained in the group R₁ is substituted, p    is not zero;    and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids, for example hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates,trifluoroacetates, acetates, citrates, succinates, tartrates, malates,lactates, fumarates and maleates.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts and their pharmaceutically acceptable solvates.

It is to be understood that when L is a single bond , the compounds ofthe invention have the general structure (IA) and when L is a doublebond the compounds of the invention have the general structure (IB)

It will be appreciated by those skilled in the art that the compounds offormula (IA) contain at least one chiral centre (namely the carbon atomshown as * in formula (I)) and may be represented by formula (1a) and(1b).

The wedge bond indicates that the bond is above the plane of the paper.The broken bond indicates that the bond is below the plane of the paper.

The configuration shown for the chiral carbon indicated as * in formula(1a) is β and in formula (1b) is α.

Further asymmetric carbon atoms are possible in the compounds of formula(I) when R₃ and R₄ are not the same group.

It is to be understood that all stereoisomeric forms including allenantiomers and mixtures thereof are encompassed within the scope of thepresent invention and the reference to compound of formula (I) includeall stereisomeric forms unless otherwise stated.

It will be appreciated by those skilled in the art that the compounds offormula (IB) can exist in E and/or Z conformation and the inventionincludes all such isomers and mixtures thereof.

The term C₁₋₄ alkyl as used herein as a group or a part of the grouprefers to a straight or branched alkyl group containing from 1 to 4carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, 1 methylethyl or 2-methylpropyl.

The term halogen refers to fluorine, chlorine, bromine or iodine.

The term C₃₋₇ cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

When R₁ is a 5 or 6 membered heteroaryl group according to the inventionthis includes furanyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl,1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl,1,2,5-thiadiazolyl, 1,2,3,6-tetrahydro-4-pyridinyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4 oxadiazolyl, 1,2,5-triazinylor 1,3,5-triazinyl and the like.

The term 4, 5 or 6 membered heterocyclic group refers to 4, 5 or 6 ringmember, containing at least one heteroatom selected from oxygen, sulphuror nitrogen, which may be saturated or unsaturated. Examples of suchgroups include azetidinyl, piperidyl, 2-oxodihydrofuranyl, piperazinyl,1,2,3,6-tetrahydro-4-pyridinyl, morpholinyl, pyrazolidinyl, 1,2dihydro-3H-pyrazolyl, imidazolidinyl or pyrrolidinyl and the like.

The term C₁₋₄ alkoxy group may be a straight chain or a branched chainalkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy.

R is preferably halogen (e.g. fluorine or chlorine) and/or a C₁₋₄ alkyl(e.g. methyl) group and n is preferably an integer from 1 to 2.

R₁ is preferably piperidyl, morpholinyl, 1,2,3,6-tetrahydro-4-pyridinyl,pyridyl or pyrrolidinyl.

When R₁ is substituted, preferably is substitued by one or two groupsselected from halogen (e.g fluorine), C₁₋₄ alkyl (e.g. methyl) or ethylC₁₋₄alkoxy.

R₂ is preferably hydrogen or methyl.

R₃ is preferably hydrogen or methyl.

R₄ is preferably hydrogen, methyl or together with R₃ is cyclopropyl.

R₅ is preferably trifluoromethyl, methyl, methoxy, bromine, chlorine orfluorine atom and m is preferably an integer from 1 to 2.

Preferred compounds of the invention are those wherein R is halogen(e.g. fluorine or chlorine) and/or a C₁₋₄ alkyl (e.g. methyl) group andn is an integer from 1 to 2; R₁ is piperidyl, 2-morpholinyl,1,2,3,6-tetrahydropyridinyl, pyridyl or pyrrolidinyl and wherein R₁ isoptionally substituted by one or two groups selected from halogen (e.gfluorine), C₁₋₄ alkyl (e.g. methyl) or ethylC₁₋₄ alkoxy; R₂ and R₃ areindependently hydrogen or methyl; R₄ is hydrogen, methyl or togetherwith R₃ is cyclopropyl and R₅ is trifluoromethyl, methyl, methoxy,bromine, chlorine or fluorine atom and q is preferably an integer from 1to 2.

Specific preferred compounds according to the invention are:

-   N-(3,5Bis-trifluoromethyl-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;-   N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;-   N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;-   N-[1-(3,5-Dichloro-phenyl)ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-[1-(2-methoxyethyl)    piperidin-4-yl]-propionamide;-   N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-{1-[2-(methyloxy)ethyl]-4-piperidinyl}propionamideN-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propanamide;-   N-{1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-3-(4-fluorophenyl)-3-(4-piperidinyl)propionamide;-   N-{[3-bromo-4-(methyloxy)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;-   N-[(3,5-dimethylphenyl)methyl-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;-   N-[(3,4-dibromophenyl)methyl-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;-   N-[(3-fluoro-2-methylphenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;-   N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl-}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;-   N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-[(3,5-dibromophenyl)methyl]-3-(3,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   3-(4-chlorophenyl)-N-[3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl-N-methyl-3-(3-piperidinylidene)propionamide;-   N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide;-   N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinyl)propionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide;-   N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide;-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl)-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinyl)propionamide;-   N-[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)propionamide;    and enantiomers, diastereiosomers, pharmaceutically acceptable salts    (e.g hydrochloride) and solvates thereof.

Particular specific preferred compounds according to the invention are:

-   N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide(diastereoisomer    1);-   N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide    (diastereoisomer 2);-   N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide    (diastereoisomer 1;-   N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide    (enantiomer 2);-   N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide    (diastereoisomer A);    and pharmaceutically acceptable salts (e.g hydrochloride) and    solvates thereof.

The compounds of the invention are antagonists of tachykinin receptors,including substance P and other neurokinins, both in vitro and in vivoand are thus of use in the treatment of conditions mediated bytachykinins, including substance P and other neurokinins.

Tachykinins are a family of peptides that share a commoncarboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are activelyinvolved in the physiology of both lower and advanced lifeforms. Inmammalian lifeforms the main tachykinins are subtance P(SP), NeurokininA (NKA) and Neurokinin B (NKB) which act as neurotransmitters andneuromodulators. Mammalian tachykinins may contribute to thepathophysiology of a number of human diseases.

Three types of tachykinins receptors have been identified, namelyNK1(SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) whichare widely distributed throughout the central nervous (CNS) andperipheral nervous system.

Particularly the compounds of the invention are antagonists of the NK1receptor.

The compounds of the present invention also have activity as selectiveserotonin reuptake inhibitors (hereinafter referred to as SSRIs) and arethus of use in the treatment of conditions mediated by selectiveinhibition of the serotonin reuptake transporter protein.

Thus the compounds of the present invention combine dual activity astachykinin antagonists, including substance P and other neurokinins, andas SSRIs. In particular, the compounds of the invention combine dualactivity as NK1 receptor antagonists and as SSRIs.

NK₁-receptor binding affinity has been determined in vitro by measuringthe compounds' ability to displace [3H]—substance P(SP) from recombinanthuman NK₁ receptors expressed in Chinese Hamster Ovary (CHO) cellmembranes.

CHO cell membranes were prepared by using a modification of the methoddescribed by Beattie D. T. et al. (Br. J. Pharmacol, 116:3149-3157,1995). Briefly, ligand binding was performed in 0.2 ml of 50 mM HEPES,pH 7.4, containing 3 mM MnCl₂, 0.02% BSA, 0.5 nM [³H]-Substance P (30÷56Ci/mmol, Amersham), a final membrane concentration of 20÷30 μg ofprotein/ml, and the test compounds. The incubation proceeded at roomtemperature for 40 min and stopped by filtration. Non-specific bindingwas determined using excess of substance P (1 μM) and represents about6÷10% of the total binding.

NK₁-receptor binding affinity has been also determined in vitro in abinding Scintillation proximity assay (SPA) by measuring compounds'ability to displace [125I]Tyr8-Substance P(SP) from recombinant humanNK₁ receptors expressed in Chinese Hamster Ovary (CHO) cell membraneprepared as described above. Briefly, polystrene Leadseeker WGA-SPAbeads (Amersham Biosciences) was mixed with cell membrane in abead/membrane ratio of 100:1 (w/w) in assay buffer (75 mM Tris pH 7.8,75 mM NaCl, 4 mM MnCl2, 1 mM EDTA, 0.05% Chaps, 1 mM PMSF). The mixturewas placed on ice for 30 minutes to allow the formation of membrane/beadcomplex before BSA was added to a final concentration of 1%. Afteranother 30 minutes incubation on ice, the bead/membrane complex waswashed twice and suspended in assay buffer. [125I]Tyr8-Substance P (2200Ci/mmol, PerkinElmer) was then added to the bead/membrane complex with afinal concentration of 0.4 nM. 30 ul of the resulting mixture was thendispensed to each well of Nalgen NUNC 384-well plate with 1 ul compoundpre-dispensed in DMSO. The plates were then sealed and pulse spin at1100 rpm. After 3 hours incubation at room temperature with shaking, theplates were spin for 2 min at 1100 rpm and measured in Viewlux imager(PerkinElmer) for 5 minutes with a 618-nm filter. Inhibition of[125I]Tyr8-Substance P binding to NK₁-receptor was measured by thereduction of luminescent signal. IC50 of each compound was determined byan 11-point 3×-dilution inhibition curve. pKi was calculated using Kd of[125I]Tyr8-Substance P determined in a separate experiment.

Compounds of the invention were further characterised in a functionalassay for the determination of their effect to inhibit the intracellularcalcium increase induced by SP in Human-NK₁-CHO cells using FLIPRtechnology. Briefly, after 30 min incubation with the cytoplasmiccalcium indicator Fluo-4 AM (2 μM), cells were washed and incubated inthe absence or presence of three different concentrations of antagonistfor 60 min, at 37° C. in Hank's balanced salts with 20 mM Hepes and thennon-cumulative concentration-response curves of SP (2 pM-300 nM) wasperformed. The potency of the antagonist (pK_(B) value) was calculatedfrom Schild's analysis.

The ability to bind at the serotonin transporter may be determined usingone of the following conventional binding or uptake assays.

The inhibitory activity of the compounds at the human SerotoninTransporter(hSERT) has been determined in vitro using hSERT-LLCPK cells(LLCPK cells tranfected with the h SERT). The cells have been platedonto 96-well plates (10000 cells/well). After 24 hr, cells have beenwashed in uptake buffer (Hank's balanced salt solution+20 mM Hepes) andpre-incubated for 10 min at RT with 50 μl of buffer containing the testcompounds. 50 μl of 50 nM [3H] Serotonin (5HT) solution (finalconcentration: 25 nM [3H] 5HT) have been added and plates have beenincubated for 7 min at RT, during which cells take up radiolabelled 5HT.Aspirating the solution and rapidly washing the cells with cold bufferhas terminated the uptake.

The amount of radioactive 5HT incorporated in the cells has been thenmeasured by adding the scintillation cocktail directly onto the cellsand reading the plate in the Top Count. The data have been digitallyprocessed to obtain the pIC50 values of the antagonists.

The inhibitory activity of the compounds at the rat SerotoninTransporter(rSERT) has been determined in vitro using rSERT-LLCPK cells(LLCPK cells tranfected with the rat SERT). The cells have been platedonto 96-well plates (60000 cells/well). After 24 hr. cells have beenwashed in uptake buffer (Hank's balanced salt solution+20 mM Hepes) andpre-incubated for 10 min at RT with 50 μl of buffer containing the testcompounds. 50 μl of 50 nM [3H] Serotonin (5HT) solution (finalconcentration: 25 nM [3H] 5HT) have been added and plates have beenincubated for 7 min at RT, during which cells take up radiolabelled 5HT.Aspirating the solution and rapidly washing the cells with cold bufferhas terminated the uptake.

The amount of radioactive 5HT incorporated in the cells has been thenmeasured by adding the scintillation cocktail directly onto the cellsand reading the plate in the Top Count. The data have been digitallyprocessed to obtain the pIC50 values of the antagonists. The pKi valueshave been calculated using the Chen-Prusoff equation.

The action of the compounds of the invention at the NK₁ receptor and/orserotonin transporter may be determined by using conventional animalmodels. Thus, the ability to bind at the NK₁ receptor and/or serotonintransporter was determined using the guinea pig pup isolation callsmodel as described by Pettijohn, Psychol. Rep., 1979 and Rupniak et al.,Neuropharmacology, 2000.

Compounds of the invention are useful in the treatment of CNS disordersand psychotic disorders, in particular in the treatment or prevention ofdepressive states and/or in the treatment of anxiety as defined in, butnot restricted to, Diagnostic Statistical of Mental Disorder (DSM) IVedition edit by American Psychiatric Association and InternationalClassification Diseases 10th revision (ICD10).

Thus, for example, depressive states include Major Depressive Disorders(MDD), including bipolar depression, unipolar depression, single orrecurrent major depressive episodes, recurrent brief depression, with orwithout psychotic features, catatonic features, melancholic featuresincluding anorexia, weight loss, atypical features, anxious depression,cyclothymic or postpartum onset.

Other mood disorders encompassed within the term major depressivedisorders include dysthymic disorders with early or late onset and withor without atypical features, neurotic depression, post-traumatic stressdisorders and social phobia; dementia of the Alzheimer's type, withearly or late onset, with depressed mood; vascular dementia withdepressed mood; mood disorders induced by alcohol, amphetamines,cocaine, hallucinogens, inhalants, opioids, phencydidine, sedatives,hypnotics, anxiolytics and other substances; schizoaffective disorder ofthe depressed type; and adjustment disorder with depressed mood. Majordepressive disorders may also result from a general medical conditionincluding, but not limited to, myocardial infarction, diabetes,miscarriage or abortion, etc.

The term anxiety includes anxiety disorders, such as panic disorderswith or without agoraphobia, agoraphobia, phobias, for example, socialphobias or agoraphobia, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorders, generalised anxietydisorders, acute stress disorders and mixed anxiety-depressiondisorders.

Compounds of the invention are useful as analgesics. In particular, theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of the cognitive disorders. Cognitive disorders includedementia, amnestic disorders and cognitive disorders not otherwisespecified.

Furthermore, compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds) or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines, in the treatment of addiction to cocaine, sedativeipnotic, amphetamine or amphetamine-related drugs (e.g.dextroamphetamine, methylamphetamine) or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular, they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment orprevention of schizophrenic disorders including paranoid schizophrenia,disorganised schizophrenia, catatonic schizophrenia, undifferentiatedschizophrenia, residual schizophrenia.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome,gastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia (such asulcer-like dyspepsia, dysmotility-like dyspepsia and unspecifieddyspepsia) chronic constipation; skin disorders such as psoriasis,pruritis and sunburn; vasospastic diseases such as angina, vascularheadache and Reynaud's disease; cerebral ischeamia such as cerebralvasospasm following subarachnoid haemorrhage; fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis; disordersrelated to immune enhancement or suppression such as systemic lupuserythematosus and rheumatic diseases such as fibrositis; and cough.

The compounds of the invention are also useful in premenstrual dysphoricdisorder (PMDD), in chronic fatigue syndrome and Multiple sclerosis.Compounds of the invention have been found to exhibit anxiolytic andantidepressant activity in conventional tests. For example in Guinea pigpups separation-induced vocalisations (Molewijk et al., 1996).

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins (including substance P and otherneurokinins) and/or by selective inhibition of serotonin reuptake.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the treatment of conditions mediated by tachykinins(including substance P and other neurokinins) and/or by selectiveinhibition of the serotonin reuptake transporter protein.

In a further aspect there is provided the use of a compounds of formula(I) or a pharmaceutically acceptable salt or solvate thereof in thepreparation of a medicament for use in the treatment of depressionand/or anxiety.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins and/or by selective inhibition of the serotonin reuptaketransporter protein comprising administration of an effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention is provided a method forthe treatment of a mammal, including man, in particular in the treatmentof depression and/or anxiety which method comprises administration of aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Thus for parenteral administration a daily dose will typically be in therange of 1 to about 100 mg, preferably 1 to 80 mg per day. For oraladministration a daily dose will typically be within the range 1 to 300mg e.g. 1 to 100 mg.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆ R₇, R₈, L, m, n, p andq have the meaning as previously defined for compounds of formula (I)unless otherwise stated.

Compounds of formula (I) may be prepared by reaction of of an activatedderivative of the carboxylic acid (II), wherein R₁ has the meaningpreviously defined or is a protected group thereof, with amine (III)

wherein R₂ is C₁₋₄ alkyl or a nitrogen protecting group, followed wherenecessary by removal of any protecting group.

Suitable activated derivatives of the carboxyl group include the acylhalide, mixed anhydride, activated ester such as thioester or thederivative formed between the carboxylic acid group and a coupling agentsuch as that used in peptide chemistry, for example carbonyl diimidazoleor dicyclohexylcarbodiimide.

The reaction is preferably carried out in an aprotic solvent such ashydrocarbon, halohydrocarbon such as dichloromethane or an ether such astetrahydrofuran.

The activated derivatives of the carboxylic acid (II) may be prepared byconventional means. A particular suitable activated derivative for usein this reaction is O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate.

Compounds of formula (II), wherein L is a single bond, may be preparedby reaction of a cyano derivative (IV), wherein R₉ is a suitablecarboxyl protecting group, with an acid such as for example concentratedsulfuric acid, followed, if it is still necessary, by removal of thecarboxyl protecting group R₉

The reaction is conveniently carried out in a solvent such as aceticacid and heating the reaction mixture up to 150°

Suitable carboxyl protecting groups R₉ for use in this reaction includealkyl, such as methyl or ethyl, trichloroalkyl, trialkylsilylalkyl, orarylmethyl groups such as benzyl, nitrobenzyl or trityl.

In one embodiment of the invention compounds of formula (II) wherein Lis a single bond may be prepared by reduction of a compound of formula(V),

with a suitable reducing agent such as hydrogen in the presence of acatalyst such as platinum oxide. or palladium on carbon. Alternativelythe reduction may be carried out with alkaline metal such as Mg. Thereduction is carried out in a suitable solvent such as alchool (e.gmethanol or ethanol) at room temperature, followed by the removal of thecarboxyl protecting group R₉.

Compound of formula (V) may be prepared by reaction of a keto compoundof formula (VI)

with an appropriate phosphorus reagent capable of converting the groupC(O) into the group (VII).

In one embodiment of this process the reaction may be carried out usinga phosphorus ylide of formula (VIII)

wherein R₈ is an alkyl or phenyl group.

The reaction is carried out in an aprotic solvent such astetrahydrofuran, acetonitrile or dimethylformamide at a temperatureranging from −20° C. to the reflux temperature of the solvent.

In a further embodiment of the invention compounds of formula (II),wherein L is a double bond, may be prepared by reduction followed byelimination of the leaving group of a compound of formula (V), whereinthe carbon atom of the group R1 linked to the carbon atom *, issubstituted by a leaving group such halogen (e.g fluorine, bromine ortosyl)

The reaction may be carried out with alkaline metal such as Mg in asuitable solvent such as alcohol (e.g methanol or ethanol) at roomtemperature.

Compounds of formula (IV) may be prepared by reaction of a compound offormula (IX) with a compound of formula (X), wherein X is a halogengroup (i.e bromine).

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon (i.e toluene) and at a temperature within the range 0-25° C.

Compounds of formula (IX) may be prepared by reaction of a compounds offormula (XI) with a cyano derivative (XII).

Compounds of formulae (VI) (X) (XI) and (XII) are known compounds or maybe prepared according to the procedure used for known compounds.

Thus compounds of formula (VI) may be prepared according to theprocedure described by Robert L. Duncan, et al. Journal. Med Chem (1970)Vol 13, no. 1, 1-6.

Thus compounds of formula (X) may be prepared according to the proceduredescribed by Jones L A et al., J. Organomet. Chem. (1985), 284 (2),159-169.

Compounds of formula (XI) may be prepared according to the proceduredescribed by Itani, Hiromichi et al. Bioorganic & Medicinal ChemistryLetters (2002), 12(5), 799-802.

Compounds of formula (XII) may be prepared according to the proceduredescribed by Lei, Yi Xiong; et al. Journal of Organic Chemistry (2003),68(3), 947-959.

Examples of suitable nitrogen protecting groups used for preparingcompounds and or intermediates of the present invention includealkoxycarbonyl e.g. t-butoxycarbonyl, benzyloxycarbonyl, arylsulphonyle.g. phenysulphonyl or 2-trimethylsilylethoxymethyl.

Protection and deprotection may be effected using conventionaltechniques such as those described in “Protective Groups in OrganicSynthesis 2^(nd) Ed.” by T. W. Greene and P. G. M. Wuts (John Wiley andSons, 1991) and as described in the examples hereinafter.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, for example, specific enantiomers of the compounds of formula (I)may be obtained from the corresponding enantiomeric mixture of acompound of formula (I) using chiral HPLC procedure.

The chiral amine (III) may be prepared from the corresponding racemicamine (III) using any conventional procedures such as salt formationwith a suitable optically active acid such as for exampledi-p-toluoyl-D-tartaric acid or di-p-toluoyl-L-tartaric acid, or usingchiral HPLC procedure.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether, tert-butylmethyl ether ortetrahydrofuran).

Melting points (m.p.) were determined on a Buchi m.p. apparatus and areuncorrected. R.T. or r.t. refer to room temperature.

Infrared spectra (IR) were measures in chloroform or nujol solutions ona FT-IR instrument. Proton Magnetic Resonance (NMR) spectra wererecorded on Varian instruments at 400 or 500 MHz, on Bruker instrumentat 300 MHz, chemical shifts are reported in ppm (δ) using the residualsolvent line as internal standard. Splitting patterns are designed as s,singlet; d, double; t, triple; q, quartet; m, multiplet; b, broad. TheNMR spectra were recorded at temperature ranging from 25 to 60° C.,where not specified the spectra are recorded at 25° C.; when more thanone conformer were detected the chemical shifts for the most abundantone is reported. Mass spectra (MS) were taken on a VG Quattro massspectrometer. In the mass spectra the more abundant peak or themolecular ion peak is reported. Optical rotations were determined at 20°C. with a Jasco DIP360 instrument (I=10 cm, cell volume=1 mL, λ=589 nm).Flash silica gel chromatography was carried out over silica gel 230-400mesh supplied by Merck AG Darmstadt, Germany. T.I.c. refers to thinlayer chromatography on 0.25 mm silica gel plates (60F-254 Merck) andvisualized with UV light and/or ninhydrine.

For phase separations performed by using microfiltration device: phaseseparation cartridge with polypropylene frit by Whatman and Alltech. Forpurifications carried out by using SCX: SCX-cartridges (loading 0.75mmol\g) by Varian.

Solutions were dried over anhydrous sodium sulphate.

Methylene chloride was redistilled over calcium hydride andtetrahydrofuran was redistilled over sodium.

The following abbreviation are used in the text: AcOEt=ethyl acetate,ACN=acetonitrile, CH=cyclohexane, DCM=methylene chloride,DIPEA=N,N-diisopropylethylamine, DMF=N,N′-dimethylformamide,Et2O=diethyl ether, EtOH=ethanol, MeOH=methanol TEA=triethylamine,THF=tetrahydrofuran.

Enantiomer 1, enantiomer 2, diastereoisomer 1, diastereoisomer 2,diastereoisomer 3 or diastereoisomer 4 refer to a single enantiomer or asingle diastereoisomer respectively, whose absolute stereochemistry wasnot characterised.

Isomer 1 and isomer 2 refer to isomers whose E or Z conformation at thedouble was not characterised.

Diastereoisomer A or diastereoisomer B refers to mixture of twodiastereoisomers whose absolute stereochemistry was not characterised.

Intermediate 1

Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

A solution of di-tert-butyl-dicarbonate (7.07 mg) in anhydrous DCM (20mL) was added to a solution of ethyl isonipecotate (5 mL) in anhydrousDCM (40 mL) previously cooled to 0° C. under a Nitrogen atmosphere. Thesolution was stirred at r.t. overnight, then it was washed with 1Nhydrochloric acid solution and brine. The organic phase was dried andconcentrated in vacuo to give the title compound (8 g) as a pale yellowoil.

T.I.c.: CH/AcOEt 1:1, Rf=0.67.

NMR (CDCl₃): δ (ppm) 4.11 (q, 2H); 3.96 (m, 2H); 2.8 (m, 2H); 2.38 (m,1H); 1.85 (m, 2H); 1.6 (m, 2H); 1.42 (s, 9H); 1.25 (t, 3H).

Intermediate 2

Hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester

Lithium aluminium hydride (1M solution in THF—17.8 mL) was added to asolution of intermediate 0.1 (8.0 g) in anhydrous THF (80 mL) previouslycooled to 0° C. under a Nitrogen atmosphere. The mixture was stirred at0° C. for 20 minutes, then it was treated with water (0.7 mL), 1M sodiumhydroxide solution (0.7 mL) and water (2 mL). The inorganic salts werefiltered off and the organic layer was concentrated in vacuo to give thetitle compound (7.0 g) as a yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.25 (detection with ninhydrine).

NMR (CDCl₃): δ (ppm) 4.1 (m, 2H); 3.71 (m, 1H); 3.45 (m, 2H); 2.67 (m,2H); 1.83 (m, 1H); 1.65 (m, 2H); 1.44 (s, 9H); 1.15 (m, 2H).

Intermediate 3

4-Formyl-piperidine-1-carboxylic acid tert-butyl ester

Method A

2,2,6,6-Tetramethylpiperidin-1-yl-oxy (free radical, TEMPO—0.486 g) andiodobenzene diacetate (11.05 g) were added to a solution of intermediate2 (7.0 g) in anhydrous DCM (40 mL). The mixture was stirred at r.t.overnight, then it was washed with a 20% sodium thiosulphate solution(50 mL) and brine.

The organic phase was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt 7:3) to give the titlecompound (4.76 g) as a pale yellow foam.

Method B

Diisobutylaluminium hydride (1M in toluene—8.6 mL) was dropped into asolution of intermediate 1 (1 g) in anhydrous toluene (13 mL) previouslycooled to −78° C. under a Nitrogen atmosphere over 30 minutes. Thesolution was stirred at −78° C. for 2 hours, then it was quenched with a10% sodium hydroxide solution (16 mL) at −78° C. The mixture was allowedto warm to r.t. and the layers were separated. The organic layer waswashed with a 10% sodium hydroxide solution and brine, dried andconcentrated in vacuo to give the title compound (0.7 g) as yellow foam.

T.I.c.: CH/AcOEt 7:3, Rf=0.35 (detection with ninhydrine).

NMR (CDCl₃): δ (ppm) 9.63 (s, 1H); 3.98 (m, 2H); 2.89 (m, 2H); 2.35 (m,1H); 1.85 (m, 2H); 1.57 (m, 2H).

Intermediate 4

4-(2Cyano-2-ethoxycarbonyl-vinyl)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of intermediate 3 (4.5 g), ethyl cyanoacetate (2.47 mL),ammonium acetate (0.813 g) and acetic acid (1.27 mL) in anhydroustoluene (90 mL) was heated to 80° C. for 3 hours, then it was allowed tocool to r.t. and washed with water, 1N sodium hydroxide solution andbrine. The organic phase was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (from CH to CH/AcOEt8:2) to give the title compound (5.5 g) as a white solid.

T.I.c.: CH/AcOEt 7:3, Rf=0.45 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm) 7.6 (d, 1H); 4.24 (q, 2H); 3.96 (bd, 2H);2.8-2.71 (m, 3H); 1.61 (bd, 2H); 1.47-1.38 (bd, 2H); 1.39 (s, 9H); 1.25(t, 3H).

MS (ES/+): m/z=309 [M+H]⁺.

Intermediate 5

4-[2-Cyano-2-ethoxycarbonyl-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of 4-fluorophenyl magnesium bromide (2M in Et2O—12.16 mL) inanhydrous Et2O (5 mL) was dropped into a solution of intermediate 4 (2.5g) in anhydrous Et2O (20 mL) previously heated to reflux under aNitrogen atmosphere. The mixture was diluted with further Et2O (10 mL)and heated to reflux for 30 minutes. The mixture was allowed to warm tor.t. and treated with 3N sulfuric acid solution (15 mL). The mixture wasstirred at r.t. for 30 minutes, then AcOEt was added and the layers wereseparated. The aqueous layer was extracted with further AcOEt. Thecombined organic extracts were washed with a saturated sodium hydrogencarbonate and brine, then dried and concentrated in vacuo. The residuewas purified by flash chromatography (from CH to CH/AcOEt 8:2) to givethe title compound (2.47 g—diastereoisomeric mixture) as a white foam.

T.I.c.: CH/AcOEt 7:3, Rf=0.38 (detection with ninhydrine).

NMR (d₆-DMSO—80° C.): δ (ppm) 7.32 (dd, 2H); 7.15 (t, 2H); 4.65 (d, 1H);4.0 (q; 3H); 3.83 (m, 1H); 3.1 (dd, 1H); 2.76 (m, 1H); 2.63 (m, 1H);1.95 (m, 1H); 1.87 (m, 1H); 1.38 (s, 9H); 1.2 (m, 1H); 1.14 (m, 1H);0.92 (m, 1H).

MS (ES/+): m/z=405 [M+H]⁺.

Intermediate 6

4-[2-Carboxy-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylic acidtert-butyl ester

Method A

A mixture of intermediate 5 (2.4 g) in acetic acid (30 mL), concsulfuric acid (8 mL) and water (9 mL) was heated to 140° C. for 2.5hours. The solution was allowed to cool to r.t. and dropped into a 2.5Msodium hydroxide solution (300 mL). Then, di-tert-butyl-dicarbonate(1.35 g) was added and the resulting mixture was stirred at r.t.overnight. It was cooled to 0° C. and treated with 3M hydrochloric acidsolution until pH=6-7 and then extracted many times with AcOEt. Thecombined organic extracts were washed with brine, dried and concentratedin vacuo. The residue was purified by flash chromatography (CH/AcOEtfrom 1:1 to 2:8) to give the title compound (0.12 g) as a pale yellowfoam.

Method B

A 3M potassium hydroxide solution (1.5 mL) was added to a solution ofintermediate 9 (90 mg) in ethanol (2 mL). The mixture was heated inmicrowave (300W, P=300 p.s.i.) at 150° C. for 40 minutes. The solutionwas allowed to cool to r.t., acidified to pH=5 with a buffer solutionpH3 (citrate-hydrochloric acid buffer solution purchase from Fluka) andextracted with AcOEt. The organic extract was dried and concentrated invacuo to give the title compound (58 mg) as a white foam.

Method C

A solution of lithium hydroxide monohydrate (1.78 g) in water (27 mL)was added to a solution of intermediate 12 (3.1 g) in MeOH (100 mL). Themixture was heated to 80° C. for 1 hour, then it was allowed to cool tor.t., diluted with water and concentrated to half volume. The residuewas acidified with 3M hydrochloric acid solution and extracted withAcOEt. The organic layer was dried and concentrated in vacuo to give thetitle compound (2.7 g) as a white foam.

T.I.c.: CH/AcOEt 1:1, Rf=0.2 (detection with ninhydrine).

IR (nujol, cm⁻¹): 3200 (COOH), 1732 and 1690 (C═O).

NMR (d₆-DMSO): δ (ppm) 11.94 (bs, 1H); 7.2 (dd, 2H); 7.08 (dd, 2H);3.95-2.6 (2m, 4H); 2.83-2.72 (m, 2H); 2.5 (m, 1H); 1.59 (m, 1H); 1.34(s, 9H); 1.72-0.94 (m, 2H); 1.22-0.82 (m, 2H).

Intermediate 7

4-[2-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl)]-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

DIPEA (0.116 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.071 g) were added to a solution of intermediate 6(0.06 g) in anhydrous DMF (5 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes, (3,5-bis-trifluoromethyl-benzyl)-methylaminehydrochloride (0.1 g) was added. The mixture was stirred at r.t. for 4hours, then it was diluted with AcOEt and washed with a 5% sodiumhydrogen carbonate solution and brine. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 7:3) to give the title compound (0.062 g) as acolourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.35.

IR (nujol, cm⁻¹): 1684 and 1645 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.95 (s, 1H); 7.7 (s, 2H); 7.2 (dd, 2H); 7.0 (dd,2H); 4.54 (q, 2H); 3.94-3.93 (2d, 2H); 3.3 (m, 1H); 3.01-2.98 (m, 1H);2.96 (s, 3H); 2.81-2.75 (m, 2H); 1.74-1.58 (m, 2H); 1.34 (s, 9H);1.27-1.18 (m, 2H); 0.99-0.76 (2q, 2H).

MS (ES/+): m/z=591 [M+H]⁺.

Intermediate 8

4-[2-[(3,5-Dichloro-benzyl)-methyl-carbamoyl)]-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

DIPEA (0.116 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.071 g) were added to a solution of intermediate 6(0.06 g) in anhydrous DMF (5 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes, (3,5-dichloro-benzyl)-methylamine hydrochloride(0.077 g) was added. The mixture was stirred at r.t. for 4 hours, thenit was diluted with AcOEt and washed with a 5% sodium hydrogen carbonatesolution and brine. The organic layer was dried, concentrated in vacuoand the residue was purified by flash chromatography (CH/AcOEt 7:3) togive the title compound (0.048 g) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.31.

IR (nujol, cm⁻¹): 1688 and 1646 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.43 (s, 1H); 7.22 (dd, 2H); 7.05 (dd, 2H); 6.98(s, 2H); 4.37 (q, 2H); 3.9 (2d, 2H); 3.0-2.71 (m, 4H); 2.9 (s, 3H);1.77-1.59 (m, 2H); 1.34 (s, 9H); 1.345-1.18 (m, 2H); 1.02-0.79 (2q, 2H).

MS (ES/+): m/z=523 [M+H]⁺.

Intermediate 9

4-[2-Cyano-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylic acidtert-butyl ester

A mixture of intermediate 5 (0.35 g), sodium chloride (17.5 mg) andwater (35 L) in dimethylsulfoxide (3 mL) was heated to 160° C. for 2hours. The mixture was allowed to cool to r.t., diluted with water andextracted with AcOEt. The organic layer was dried and concentrated invacuo. The residue was purified by flash chromatography (from CH toCH/AcOEt 7:3) to give the title compound (0.27 g) as a yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.61 (detection with ninhydrine).

IR (nujol, cm⁻¹): 2245 (C≡N), 1681 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.31 (dd, 2H); 7.16 (dd, 2H); 3.95-2.6 (2m, 4H);2.9-2.8 (m, 2H); 2.7 (m, 1H); 1.7 (m, 1H); 1.35 (s, 9H); 1.74-0.99 (m,2H).

MS (ES/+): m/z=333 [M+H]⁺.

Intermediate 10

4-(4-Fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester

A solution of intermediate 3 (126.6 mg) in anhydrous Et2O (2 mL) wasdropped into a solution of 4-fluorophenyl magnesium bromide (2M inEt2O—1 mL) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. At the end of the addition the mixture was allowedto warm to r.t. and stirred at 23° C. for 30 minutes. The mixture wasquenched with a saturated ammonium chloride solution (2 mL). The aqueouslayer was further extracted with AcOEt. The combined organic extractswere washed with brine, dried and concentrated in vacuo to give4-[(4-fluoro-phenyl)hydroxy-methyl]-piperidine-1-carboxylic acidtert-butyl ester (292.3 mg—T.I.c.: DCM/AcOEt 9:1, Rf=0.4).

This material was dissolved in anhydrous DCM (4 mL) and treatedportion-wise with Dess Martin periodinane (254.5 mg) under a Nitrogenatmosphere. The brown solution was stirred at r.t. for 3 hours, thenfurther Dess Martin periodinane (127.2 mg) was added. The solution wasdiluted with Et2O (16 mL) and poured into a saturated sodium hydrogensolution (16 mL) containing sodium thiosulphate (392 mg). The mixturewas stirred for 10 minutes, then the phases were separated. The organiclayer was washed with a saturated sodium hydrogen carbonate solution.The organic layer was dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (CH/AcOEt 8:2) to give the titlecompound (58 mg) as a yellow solid.

T.I.c.: DCM/AcOEt 9:1, Rf=0.82 (detection with ninhydrine).

IR (nujol, cm⁻¹): 1685 and 1675 (C═O).

NMR (d₆-DMSO): δ (ppm) 8.07 (t, 2H); 7.35 (t, 2H); 3.96 (d, 2H); 3.62(t, 1H); 2.9 (bs, 2H); 1.74-1.39 (m, 4H); 1.39 (s, 9H).

MS (ES/+): m/z=308 [M+H]⁺, 330 [M+Na]⁺.

Intermediate 11

E-4-[2-Ethoxycarbonyl-1-(4-fluoro-phenyl)-vinyl]-piperidine-1-carboxylicacid tert-butyl ester (11a) andZ-4-[2-Ethoxycarbonyl-1-(4-fluoro-phenyl)-vinyl]-piperidine-1-carboxylicacid tert-butyl ester (11b)

Triethylphosphonoacetate (1.33 g) was added to a suspension of sodiumhydride (60% suspension in mineral oil—200 mg) in anhydrous THF (7.4 mL)previously cooled to 0° C. under a Nitrogen atmosphere. The mixture wasallowed to warm to r.t. and stirred at 23° C. for 20 minutes. Then, asolution of intermediate 10 (58 mg) in anhydrous THF (7.4 mL) was addedand the resulting solution was heated to reflux for 48 hours. Thesolution was allowed to cool to r.t., diluted with water and extractedwith Et2O. The organic layer was washed with water and brine, dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (CH/AcOEt 9:1) to give:

-   intermediate 11a (181 mg) as yellow oil;-   intermediate 11b (267 mg) as yellow oil.    Intermediate 11a:

T.I.c.: CH/AcOEt 7:3, Rf=0.64 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm): 7.2 (m, 4H); 5.67 (s, 1H); 4.13 (q, 2H); 3.76(t, 1H); 3.97-2.7 (m, 4H); 1.34 (s, 9H); 1.22 (t, 3H).

MS (ES/+): m/z=378 [M+H]⁺, 400 [M+Na]⁺.

Intermediate 11b:

T.I.c.: CH/AcOEt 7:3, Rf=0.53 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm): 7.2 (m, 4H); 5.83 (d, 1H); 3.87 (q, 2H);3.96-2.63 (m, 4H); 3.6 (m, 1H); 1.63-1.17 (m, 4H); 1.36 (s, 9H); 0.97(t, 3H).

MS (ES/+): m/z=378 [M+H]⁺, 400 [M+Na]⁺.

Intermediate 12

4-[2-Methoxycarbonyl-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester

Magnesium turnings (20.3 mg) were added to a solution of intermediate11a and 11b (63 mg) in anhydrous MeOH (1.7 mL) under a Nitrogenatmosphere with a low heating until hydrogen evolution is observed.Then, the reaction mixture was stirred at r.t. overnight, then water (2mL) and a 10% acetic acid solution were added until dissolution of themagnesium salts. The mixture was made basic until pH=8.5 with 32%ammonium hydroxide solution and extracted with Et2O. The organic phasewas washed with water and a saturated sodium hydrogen carbonatesolution, dried and concentrated in vacuo. The residue was purified byflash chromatography (CH/AcOEt 7:3) to give the title compound (37 mg)as a yellow oil.

IR (nujol, cm⁻¹): 1739 and 1694 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.08 (t, 2H); 7.2 (dd, 2H); 3.93-3.84 (dd, 2H);3.41 (s, 3H); 2.84-2.61 (q, 4H); 2.8 (m, 1H); 1.73-0.93 (m, 2H); 1.6 (m,1H); 1.34 (s, 9H); 1.21-0.84 (m, 2H).

MS (ES/+): m/z=366 [M+H]⁺.

Intermediate 13

4-[2-[1(3,5-Dichloro-phenyl)-ethyl]-methyl-carbamoyl]-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester (13a-diastereoisomer A) and4-[2-[1-(3,5-Dichloro-phenyl)-ethyl]-methyl-carbamoyl]-1-(4-fluoro-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester (13b-diastereoisomer B)

DIPEA (595 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.563 g) were added to a solution of intermediate 6(0.4 g) in anhydrous DMF (7 mL) under a Nitrogen atmosphere. Afterstirring for 30 minutes, intermediate 15 (0.256 g) was added. Themixture was stirred at r.t. overnight, then it was diluted with AcOEtand washed with a saturated ammonium chloride solution. The organiclayer was dried, concentrated in vacuo and the residue was purified byflash chromatography (CH/AcOEt 7:3) to give:

-   intermediate 13a (180 mg) as yellow oil-   intermediate 13b (180 mg) as yellow oil.    Intermediate 13a:

T.I.c.: CH/AcOEt 1:1, Rf=0.37.

NMR (d₆-DMSO): δ (ppm) 7.48 (s, 1H); 7.15 (s, 2H); 7.21 (m, 2H); 7.09(t, 2H); 5.58 (q, 1H); 4.0-3.8 (dd, 2H); 3.0-2.8 (dd, 2H); 3.0 (m, 1H);2.8 (s, 3H); 2.6 (m, 1H); 1.8-0.8 (m, 4H); 1.4-1.2 (d, 3H); 1.34 (s,9H).

Intermediate 13b:

T.I.c.: CH/AcOEt 1:1, Rf=0.30.

MS (ES/+): m/z=559 [M+Na]⁺.

Intermediate 14

3′,5′-Dichloroacetophenone

A solution of methyl iodide (4 mL) in anhydrous Et2O (40 mL) was droppedinto a suspension of magnesium (1.6 g) in anhydrous Et2O (16 mL) under aNitrogen atmosphere. At the end of the dropping, benzene (120 mL) wasadded and the Et2O eliminated with a Nitrogen flux. Then, a solution of3,5-dichlorobenzonitrile (4 g) in benzene (48 mL) was added and themixture was heated to reflux for 3 hours. The solution was cooled to 0°C. and a 6N hydrochloric add solution was added and the mixture wasstirred overnight at r.t. Water and Et2O were added and the layers wereseparated. The organic phase was washed with a saturated sodium hydrogencarbonate solution and brine, dried and concentrated in vacuo. Theresidue was purified by flash chromatography (CH/AcOEt 95:5) to give thetitle compound (2.55 g) as an orange oil.

T.I.c.: CH/AcOEt 8:2, Rf=0.64.

NMR (CDCl₃): δ (ppm) 7.75 (s, 2H); 7.6 (s, 1H); 2.55 (s, 3H).

Intermediate 15

[1-(3,5-Dichloro-phenyl)-ethyl]-methylamine

Methylamine (2M solution in MeOH—13 mL) was added to a solution ofintermediate 14 (500 mg) in MeOH (26 mL) under a Nitrogen atmosphere.The mixture was stirred at r.t. for 18 hours, then it was cooled to 0°C. and sodium borohydride (98 mg) was added. The mixture was stirred at0° C. for 2 hours, then it was quenched with water and extracted withDCM. The organic layer was dried and concentrated in vacuo to give thetitle compound (340 mg) as yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.15.

NMR (CDCl₃): δ (ppm) 7.3 (m, 3H); 3.6 (q, 1H); 2.3 (s, 3H); 1.35 (d,3H).

MS (ES/+): m/z=204 [M+H]⁺.

Intermediate 16

1-Oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester

Sodium hydride (60% suspension in mineral oil—3.6 g) was added to asolution of trimethylsulfoxonium iodide (19.8 g) in anhydrous DMSO (200mL) under a Nitrogen atmosphere. The mixture was stirred at r.t. for 1hour, then a solution of 1-(tert-butoxycarbonyl)-4-piperidone (15 g) inanhydrous DMSO (200 mL) was added. The mixture was heated to 60° C. for1.5 hours. The mixture was diluted with AcOEt (1 l) and washed withwater and ice. The layers were separated. The aqueous layer wasextracted with further AcOEt (500 mL). The combined organic extractswere washed with brine and dried. After concentration in vacuo, thecrude was purified using a Biotage column (CH/AcOEt 8:2) to give thetitle compound (14.2 g).

T.I.c.: CH/AcOEt 7:3, Rf=0.61.

IR (nujol, cm⁻¹): 1699 (C═O).

NMR (CDCl₃): δ (ppm) 3.54 (m, 2H); 3.4 (m, 2H); 2.68 (s, 2H); 1.67 (m,2H); 1.44 (s, 9H); 1.42 (m, 2H).

Intermediate 17

4-Fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A 70% solution of hydrofluoric acid in pyridine (12 mL) was addeddrop-wise to a solution of intermediate 16 (10 g) in anhydrous DCM (200mL) previously cooled to −40° C. under a Nitrogen atmosphere. After 1.5hours, further hydrofluoric acid in pyridine (6 mL) was added.

After stirring for further 15 minutes, a saturated sodium hydrogencarbonate solution was added. The layers were separated and the aqueousphase was extracted three times with further DCM. The combined organicextracts were washed with brine, dried and concentrated in vacuo to aresidue which was purified by flash chromatography (CH/AcOEt 6:4) togive the pure title compound (990 mg) and a fraction of title compound(6.01 g) impure of pyridine. Thus, this material was diluted with AcOEtand washed three times with a pH3 buffer solution and brine. The organiclayer was dried and concentrated in vacuo to give a further amount oftitle compound (5.12 g).

T.I.c.: CH/AcOEt 1:1, Rf=0.35.

NMR (d₆-DMSO): δ (ppm) 4.99 (t, 1H); 3.79 (m, 2H); 3.43 (dd, 2H); 3.01(bt, 2H); 1.8-1.4 (m, 4H); 1.43 (s, 9H).

Intermediate 18

4-Fluoro-4-formyl-piperidine-1-carboxylic acid tert-butyl ester

Dimethylsulfoxide (3.8 mL) was added to a solution of oxalyl choride(1.7 mL) in anhydrous DCM (126 mL) previously cooled to −78° C. under aNitrogen atmosphere. The solution was stirred at −78° C. for 1 hour,then a solution of intermediate 17 (2.5 g) in anhydrous DCM (36 mL) wasdropped over 1 hour. The mixture was stirred at −78° C. for 30 minutes,then TEA (7.4 mL) was added. The mixture was allowed to warm to r.t.over 1.5 hours, then it was washed with water, 5% sodium hydrogencarbonate solution and brine. The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (CH/AcOEt 6:4) to give the title compound (1.7 g).

NMR (d₆-DMSO): δ (ppm) 9.64 (d, 1H); 3.89-3.78 (m, 4H); 1.82-1.59 (m,4H); 1.39 (s, 9H).

MS (ES/+): m/z—232[M+H]⁺.

Intermediate 19

4-(2Cyano-2-ethoxycarbonyl-vinyl)-4-fluoro-piperidine-1-carboxylic acidtert-butyl ester

A round bottom flask equipped with a Dean stark apparatus was chargedwith intermediate 18 (1.4 g), ethyl cyanoacetate (0.71 mL), ammoniumacetate (233.5 mg) and acetic acid (0.35 mL) in anhydrous toluene (30mL) under a Nitrogen atmosphere. The mixture was heated to 95° C. for 4hours, then to 120° C. for 30 minutes. The mixture was allowed to coolto r.t. and further ethyl cyanoacetate (0.2 mL) was added. The mixturewas heated to 120° C. for 1 hour, then left at 90° C. overnight. Thereaction mixture was allowed to cool to r.t. . . . diluted with AcOEtand washed with water (20 mL), 0.5M sodium hydroxide solution (3×20 mL),water (20 mL) and brine (30 mL). The organic phase was dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound (1.33 g).

T.I.c.: CH/AcOEt 7:3, Rf=0.26 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm) 7.74 (d, 1H); 4.26 (q, 2H); 3.9 (bs, 2H); 2.98(m, 2H); 1.99 (m, 2H); 1.78 (m, 2H); 1.4 (s, 9H); 1.26 (t, 3H).

MS (ES/+): m/z=327 [M+H]⁺.

Intermediate 20

4-(2-Cyano-2-ethoxycarbonyl)-1-(4-fluoro-phenyl)-4-fluoro-piperidine-1-carboxylicacid tert-butyl ester

4-Fluorophenyl magnesium bromide (1M in THF—4.6 mL) was dropped into asolution of intermediate 19 (500 mg) in anhydrous Et2O (20 mL) over 15minutes under a Nitrogen atmosphere. The mixture was heated to refluxfor 40 minutes. The mixture was allowed to warm to r.t. and treated witha saturated ammonium chloride solution (15 mL) and water (15 mL). Themixture was extracted with Et2O (3×30 mL). The combined organic extractswere washed with a saturated sodium hydrogen carbonate and brine, thendried and concentrated in vacuo. The residue was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound (520 mg) as acolourless oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.26(detection with ninhydrine).

IR (nujol, cm⁻¹): 2247 (CN); 1747 and 1690 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.46 (dd, 2H); 7.2 (dd, 2H); 4.92 (d, 1H); 4.02(q, 2H); 3.87 (bm, 1H); 3.75 (bm, 1H); 3.64 (dd, 1H); 2.94 (bm, 1H); 2.8(bm, 1H); 1.64 (td, 1H); 1.54 (m, 1H); 1.44 (m, 1H); 1.36 (s, 9H); 1.03(t, 3H).

MS (ES/+): m/z=423 [M+H]⁺.

Intermediate 21

4-(2-Cyano-1-(4-fluoro-phenyl)-ethyl]-4-fluoro-piperidine-1-carboxylicacid tert-butyl ester

A mixture of intermediate 20 (500 mg), sodium chloride (20 mg) and water(130 L) in anhydrous dimethylsulfoxide (4 mL) was heated to 150° C. for1.5 hours. The mixture was allowed to cool to r.t., diluted with AcOEt(30 mL) and washed with water and brine. The organic layer was dried andconcentrated in vacuo. The residue was purified by flash chromatography(CH/AcOEt 8:2) to give the title compound (260 mg) as a colourless wax.

T.I.c.: CH/AcOEt 6:4, Rf=0.45(detection with ninhydrine).

MS (ES/+): m/z=295 [M-tBu]⁺.

Intermediate 22

4-[2-Carboxy-1-(4-fluoro-phenyl)-ethyl]-4-fluoro-piperidine-1-carboxylicacid tert-butyl ester

Method A

A 3M potassium hydroxide solution (3 mL) was added to a solution ofintermediate 21 (80 mg) in abs. EtOH (3 mL). The mixture was heated inmicrowave (300W, P=90 p.s.i.) at 150° C. for 10+10+10 minutes. Thesolution was allowed to cool to r.t., acidified to pH=5 with a pH3buffer solution (citrate-hydrochloric acid buffer solution purchase fromFluka) and 2N hydrochloric acid solution and extracted with AcOEt (3×25mL). The organic extract was dried and concentrated in vacuo to give thetitle compound (56 mg) as a white solid.

Method B

A solution of lithium hydroxide monohydrate (951 mg) in water (16 mL)was added to a solution of intermediate 37 (1.8 g) in MeOH (64 mL). Themixture was heated to 70° C. for 1.5 hours, then it was allowed to coolto r.t., diluted with AcOEt/H₂O, acidified to pH 4 with a pH3 buffersolution (citrate-hydrochloric acid buffer solution purchase from Fluka)and 1N hydrochloric acid solution. The aqueous layer was extracted withfurther AcOEt. The organic extract was dried and concentrated in vacuoto give the title compound (1.6 g) as a white solid.

T.I.c.: AcOEt 100%, Rf=0.7 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm) 12.05 (bs, 1H); 7.28 (m, 2H); 7.12 (m, 2H); 3.79(m, 2H); 3.26 (m, 1H); 2.88 (dd, 1H); 2.8 (bm, 2H); 2.67 (dd, 1H);1.8-1.4 (m, 4H).

MS (ES/+): m/z=370 [M+H]⁺, 314 [M-tBu]⁺.

Intermediate 23

4-[2-[(3,5-Dichloro-benzyl)-methyl-carbamoyl]-1-(4-fluoro-phenyl)-ethyl]-4-fluoro-piperidine-1-carboxylicacid tert-butyl ester

DIPEA (80 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (65 mg) were added to a solution of intermediate 21(56 mg) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes, 3,5-dichlorobenzyl-methylamine hydrochloride(40 mg) was added. The mixture was stirred at r.t. overnight, then itwas diluted with water (5 mL) and extracted with AcOEt (20 mL). Theaqueous layer was extracted with AcOEt (3×15 mL). The combined organicextracts were washed with brine, dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH/AcOEt 7:3) to give thetitle compound (65 mg) as a whitish foam.

T.I.c.: CH/AcOEt 4:6, Rf=0.5.

IR (nujol, cm⁻¹): 1688 and 1646 (C═O).

MS (ES/+): m/z=563 [M+Na]⁺, 465 [M-tBu-HF]⁺.

Intermediate 24

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(24a) (diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(24b) (diastereoisomer 2)

DIPEA (110 μL) andO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (104 mg) were added to a solution of intermediate 6(75 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 1 hour,(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (62 mg) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith AcOEt and washed with water. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH, then CH/AcOEt from 9/1 to 7/3) to give:

-   intermediate 24a (28 mg) as a colourless oil;-   intermediate 24b (31 mg) as a colourless oil.    Intermediate 24a:

T.I.c.: CH/AcOEt 1:1, Rf=0.55.

NMR (CDCl3): δ (ppm) 7.78 (s, 1H); 7.63 (s, 2H); 7.14 (dd, 2H); 7.00(dd, 2H); 6.00 (q, 1H); 4.16 (b, 1H); 4.04 (b, 1H); 3.08 (dd, 1H); 2.79(dd, 1H); 2.70 (m, 1H); 2.65 (dd, 1H); 2.56 (s, 3H); 2.55 (m, 1H); 1.81(m, 1H); 1.66 (m, 1H); 1.44 (s, 9H); 1.35 (bd, 1H); 1.30 (d, 3H); 1.26(m, 1H); 1.02 (m, 1H).

MS (ES/+): m/z=627 [M+Na]⁺.

Intermediate 24b:

T.I.c.: CH/AcOEt 1:1, Rf=0.48.

NMR (CDCl3): δ (ppm) 7.80 (s, 1H); 7.45 (s, 2H); 7.12 (dd, 2H); 6.96(dd, 2H); 6.01 (q, 1H); 4.16 (b, 1H); 4.04 (b, 1H); 3.10 (dd, 1H); 2.74(dd, 1H); 2.72 (dd, 1H); 2.70 (m, 1H); 2.58 (s, 3H); 2.56 (m, 1H); 1.82(m, 1H); 1.69 (m, 1H); 1.48 (d, 3H); 1.44 (s, 9H); 1.35 (bd, 1H); 1.15(m, 1H); 1.02 (m, 1H).

MS (ES/+): m/z=627 [M+Na]⁺.

Intermediate 25

1,1-dimethylethyl4-[3-[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(25a)(diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(25b)(diastereoisomer 2)

DIPEA (595 μL) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (563 mg) were added to a solution of intermediate 6(400 mg) in anhydrous DMF (7 mL) under a Nitrogen atmosphere. Afterstirring for 30 minutes,(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (339 mg) wasadded. The mixture was stirred at r.t. for 12 hours, then it was dilutedwith AcOEt and washed with a 5% sodium hydrogen carbonate solution andbrine. The organic layer was dried, concentrated in vacuo and theresidue was purified three times by flash chromatography (CH/AcOEt 7:3)to give:

-   intermediate 25a (198 mg) as a colourless oil-   intermediate 25b (165 mg) as a colourless oil    Intermediate 25a

T.I.c.: CH/AcOEt 7:3, Rf=0.40.

NMR (d₆-DMSO): δ (ppm) 8.0-7.6 (m, 3H); 5.71 (q, 1H); 3.9 (m, 2H);3.0-2.4 (m, 2H); 3.0-2.4 (m, 2H); 1.7-0.8 (m, 5H); 2.71 (s, 3H); 1.34(s, 9H); 1.34 (d, 3H).

Intermediate 25b

T.I.c.: CH/AcOEt 7:3, Rf=0.35.

NMR (d₆-DMSO): δ (ppm) 8.1-7.56 (m, 3H); 7.17 (m, 2H); 6.97 (m, 2H);5.73,(m, 1H); 3.90 (m, 2H); 3.00-2.6 (m, 3H); 3.0-2.6 (m, 2H); 1.8-0.8(m, 5H); 2.69 (s, 3H); 1.43 (d, 3H); 1.34 (s, 9H).

Intermediate 26

1,1-dimethylethyl4-[3-({1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}amino)-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

DIPEA (74 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (59 mg) were added to a solution of intermediate 6 (50mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. After stirringfor 30 minutes {1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}amine(52 mg) was added. The mixture was stirred at r.t. overnight, then itwas diluted with AcOEt (10 mL) and washed with water (10 mL), then witha 0.1M hydrochloric acid cold solution (5 mL) and finally with brine (5mL). The organic layer was dried and concentrated in vacuo to give thetitle compound (91 mg) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.52 (detection UV and with ninhydrine).

MS (ES/+): m/z=627 [M+Na]⁺.

Intermediate 27

1,1-dimethylethyl4-[3-[{1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Sodium tert-butoxide (17 mg) was added to a solution of intermediate 26(90 mg) in anhydrous DMF (1 mL) under a Nitrogen atmosphere. The yellowsolution was stirred at r.t. for 30 minutes, then iodomethane (108 μL)was added. The mixture was stirred at r.t. overnight, then it wasdiluted with AcOEt (10 mL), washed with water (5 mL) and then with brine(5 mL). The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH/AcOEt 8:2) to give thetitle compound (50 mg) as a colourless oil.

T.I.c.: CH/AcOEt 6:4, Rf=0.53 (detection UV and with ninhydrine).

MS (ES/+): m/z=519 [M-BOC+H]⁺.

Intermediate 28

1,1-dimethylethyl4-[3-[{[3-bromo-4-(methyloxy)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

DIPEA (222 μl) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoroposphate (212 mg) were added to a solution of intermediate 6(150 mg) in anhydrous DMF (1 ml). After stirring for 20 minutes,{[3-bromo-4-(methyloxy)phenyl]methyl}methylamine (108 mg). was added.The mixture was then stirred at r.t. overnight, then it was diluted withDCM (2 ml), washed with a 5% sodium hydrogen carbonate solution (1 ml),filtered on Whatman polypropilene support filter tubes, washed with anammonium chloride saturated solution (2 ml) and filtered once again onWhatman tubes. The filtrate was diluted with dry DCM (5 ml) and aportion of isocyanate polymer bound (230 mg) was added. The resultingsuspension was stirring at r.t. overnight. Then the resin was filteredoff and the mixture was concentrated in vacuo to obtain the titlecompound a as crude.

MS (ES/+): m/z=483 [M+H]⁺.

Following the same procedure described for intermediate 28,intermediates 29-32 as a crude were obtained.

Intermediate 29

1,1-dimethylethyl4-[3-[[(3,5-dimethylphenyl)methyl](methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Starting from [(3,5-dimethylphenyl)methyl]methylamine hydrochloride (87mg).

MS (ES/+): m/z=611 [M+H]⁺.

Intermediate 30

1,1-dimethylethyl4-[3-[[(3,4-dibromophenyl)methyl](methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Starting from [(3,4-dibromophenyl)methyl]methylamine (131 mg).

MS (ES/+): m/z=563 [M+H]⁺.

Intermediate 31

1,1-dimethylethyl4-[3-[[(3-fluoro-2-methylphenyl)methyl](methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Starting from [(3-fluoro-2-methylphenyl)methyl]methylamine (89 mg).

MS (ES/+): m/z=487 [M+H]⁺.

Intermediate 32

1,1-dimethylethyl4-[3-[{[2-chloro-3-(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Starting from {[2-chloro-3-(trifluoromethyl)phenyl]methyl}methylaminehydrochloride (122 mg).

MS (ES/+): m/z=563 [M+H]⁺.

Intermediate 33

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(33a) (diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(33b) (diastereoisomer 2)

DIPEA (0.08 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.092 g) were added to a solution of intermediate 22(0.08 g) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes,(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (0.065 g) wasadded. The mixture was stirred at r.t. overnight, then it was taken upwith AcOEt (30 mL) and washed with water (4×5 mL) and brine (2×5 mL).The organic layer was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt 7/3) to give:

-   intermediate 33a (0.053 g) as a white foam;-   intermediate 33b (0.058 g) as a white foam.    Intermediate 33a

T.I.c.: CH/AcOEt 6:4, Rf=0.4 (detection with ninhydrine).

MS (ES/+): m/z=645 [M+Na]⁺.

Intermediate 33b

T.I.c.: CH/AcOEt 6:4, Rf=0.35 (detection with ninhydrine).

MS (ES/+): m/z=645 [M+Na]⁺.

Intermediate 34

1,1-dimethylethyl4-[3-[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(34a) (diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(34b) (diastereoisomer 2)

DIPEA (0.08 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.092 g) were added to a solution of intermediate 22(0.08 g) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes,[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (0.065 g)was added. The mixture was stirred at r.t. overnight, then it was takenup with AcOEt (30 mL) and washed with water (4×5 mL) and brine (2×5 mL).The organic layer was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt 7/3) to give:

-   intermediate 34a (0.054 g) as a white foam;-   intermediate 34b (0.056 g) as a white foam.    Intermediate 34a

T.I.c.: CH/AcOEt 6:4, Rf=0.4 (detection with ninhydrine).

MS (ES/+): m/z=645 [M+Na]⁺.

Intermediate 34b

T.I.c.: CH/AcOEt 6:4, Rf=0.35 (detection with ninhydrine).

MS (ES/+): m/z=645 [M+Na]⁺.

Intermediate 35

1,1-dimethylethyl4-fluoro-4-[(4-fluorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of Lithyum bis(trimethylsilyl)-amide 1M in THF (13.8 mL) wasdropped into a solution of intermediate 10 (2.637 g) dissolved inanhydrous THF (170 mL) previously cooled to −78° C. under a Nitrogenatmosphere. At the end of the addition the mixture was stirred for 15min. and then allowed to warm to −10° C. and stirred for 1.5 hours. Thenthe mixture was cooled to −40° C. and N-Fluorobenzene-sulfonimide (3.53g) dissolved in anhydrous THF (28 mL) was added. The mixture was allowedto warm to r.t. in 1.5 hours, then it was treated with ammonium chloridesaturated solution. AcOEt was added, the organic layer was washed withbrine, dried and concentrated in vacuo to a residue which was purifiedby flash chromatography (from CH to CH/AcOEt 9:1) to give the titlecompound (2.15 g) as colourless oil???

T.I.c.: CH/AcOEt 9:1, Rf=0.29 (detection with ninhydrine).

MS (ES/+): m/z=270 [M-tBut+H]⁺.

Intermediate 36

1,1-dimethylethyl4-[(1E)-3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-4-fluoro-1-piperidinecarboxylate

Triethylphosphono Acetate (5.2 mL) was dropped into a sospension of NaH(60% in mineral oil 1.05 g) in anhydrous THF (66 mL) previously cooledto 0° C. under a Nitrogen atmosphere. At the end of the addition themixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 35 (2.15 g) dissolved in anhydrous THF (66 mL) was addedand the mixture was stirred at 70°. After 1 hour the mixture was allowedto reach r.t. and was treated with water and extracted with AcOEt. Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by silica cartridge (from CH/AcoEt 9:1 to CH/AcOEt 8:2) to givethe title compound (2.0 g) as a white solid. T.I.c.: CH/AcOEt 8:2,Rf=0.43 (detection with ninhydrine).

MS (ES/+): m/z=418 [M+Na]⁺.

Intermediate 37

1,1-dimethylethyl4-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

PtO2 (460 mg) was added to a solution of intermediate 36 (2.0 g) inanhydrous EtOH (180 mL) under a Nitrogen atmosphere. The reactionmixture was stirred under Hydrogen atmosphere overnight. Then furtherPtO2 (500 mg) was added and the reaction mixture was stirred underHydrogen atmosphere for 4 hours. It was filtered over a celte padwashing with AcOEt and concentrated in vacuo to a residue which waspurified by flash chromatography (CH/AcOEt 8:2) to give the titlecompound (1.8 g) as a yellow oil.

T.I.c.: CH/AcOEt 8:2, Rf=0.33 (detection with ninhydrine).

MS (ES/+): m/z=420 [M+Na]⁺.

Intermediate 38

1,1-dimethylethyl4-[3-[[(3,5-dibromophenyl)methyl](methyl)amino]-1-(4-fluorophenyl)-3-oxoproyl]-4-fluoro-1-piperidinecarboxylate

DIPEA (704 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (563 mg) were added to a solution of intermediate 22(500 mg) in anhydrous DMF (15 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes, 1-(3,5-dibromophenyl)-N-methylmethanamine (411mg) was added. The mixture was stirred at r.t. overweekend. Then furtherDIPEA (188 μL), TBTU (151 mg) and after 10 min.1-(3,5-dibromophenyl)-N-methylmethanamine (112 mg) were added and themixture was stirred for additional 3 hours. It was diluted withwater/ice and extracted with AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 8:2 to 7:3) to give the title compound(765 mg) as a white foam. T.I.c.: CH/AcOEt 6:4, Rf=0.42 (detection withninhydrine).

MS (ES/+): m/z=651 [M+Na]⁺.

Intermediate 39

1,1-dimethylethyl4-[(2,4-dichlorophenyl)(hydroxy)methyl]-1-piperidinecarboxylate

A solution of 2,4-dichloroiodobenzene (2.23 mL) in anhydrous Et2O (8 mL)was dropped into a suspension of magnesium turning (0.395 g) and fewcrystals of iodine in anhydrous Et2O (8 mL) under a Nitrogen atmosphere.The mixture was refluxed for 30 minutes, then it was allowed to cool tor.t. then cooled to 0° C. and a mixture of intermediate 3 (1.3 g) inanhydrous Et2O (8 mL) was added dropwise. At the end of the addition themixture was allowed to warm to r.t. and stirred at 23° C. for 30minutes. The mixture was quenched with ammonium chloride saturatedsolution, stirred for 10 minutes then extracted with DCM (3×50 mL). Thecombined organic extracts were concentrated in vacuo. The residue waspurified by flash chromatography (CH/AcOEt from 95:5 to 8:2) to give thetitle compound (0.9 g) as a white foam.

T.I.c.: CH/AcOEt 75:25, Rf=0.35

MS (ES/+): m/z=360 [M+H]⁺.

Intermediate 40

1,1-dimethylethyl4-[(2,4-dichlorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of mixture of intermediate 39 (0.67 g) was dissolved inanhydrous DCM (11 mL) and treated portionwise with Dess Martinperiodinane (0.79 g) under a Nitrogen atmosphere. The brown solution wasstirred at r.t. for 1.5 hours, then the solution was diluted with DCM(30 mL) and poured into a saturated sodium hydrogen carbonate solution(50 mL) containing sodium thiosulphate (2.5 g). The mixture was stirredfor 30 minutes, then the phases were separated. The organic layer waswashed with a saturated sodium hydrogen carbonate solution. The organiclayer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (CH/AcOEt (95:5 to 75:15) to give thetitle compound (0.47 g) as a colourless oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.53 (detection with ninhydrine).

MS (ES/+): m/z=358 [M+H]⁺.

Intermediate 41

1,1-dimethylethyl4-[(2,4-dichlorophenyl)carbonyl]-4-fluoro-1-piperidinecarboxylate

A solution of Lithyum bis(trimethylsilyl)-amide 1M in THF (5.1 mL) wasdropped into a solution of intermediate 40 (1.14 g) dissolved inanhydrous THF (64 mL) previously cooled to −78° C. under a Nitrogenatmosphere. After 15 min. the mixture was allowed to warm to −10° C. andstirred for 1.5 hours. The mixture was cooled to −40° C. andN-Fluorobenzene-sulfonimide (1.31 g) dissolved in anhydrous THF (11 mL)was added. The mixture was allowed to stir to r.t. for 1.5 hours andthen treated with ammonium chloride saturated solution. AcOEt was added,the organic layer was washed with brine, dried and concentrated in vacuoto a residue which was purified by flash chromatography (from CH toCH/AcOEt 9:1) to give the title compound (985 mg).

T.I.c.: CH/AcOEt 7:3, Rf=0.58 (detection with ninhydrine).

MS (ES/+): m/z=398 [M+Na]⁺.

Intermediate 42

1,1-dimethylethyl4-[1-(2,4-dichlorophenyl)-3-(ethyloxy)-3-oxo-1-propen-1-yl]-4-fluoro-1-piperidinecarboxylate

Triethylphosphono Acetate (2.1 mL) was dropped into a sospension of NaH(60% in mineral oil, 420 mg) in anhydrous THF (26 mL) previously cooledto 0° C. under a Nitrogen atmosphere. At the end of the addition themixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 41 (985 mg) dissolved in anhydrous THF (26 mL) was addedand the mixture was stirred at 65° C. for 1.5 hours and then at 70° C.for an additional hour. The mixture was allowed to reach r.t., treatedwith water and extracted with AcOEt. The organic layer was dried andconcentrated in vacuo to a residue which was purified by silicacartridge (CH/AcOEt 9:1) to give the title compound (1.1 g) as a mixtureof isomers E/Z 70:30.

T.I.c.: CH/AcOEt 9:1, Rf=0.20 (detection with ninhydrine).

MS (ES/+): m/z=468 [M+Na]⁺.

Intermediate 43

1,1-dimethylethyl4-[1-(2,4-dichlorophenyl)-3-(ethyloxy)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

PtO2 (130 mg) was added to a solution of intermediate 42 (850 mg) inanhydrous EtOH (70 mL) under a Nitrogen atmosphere. The reaction mixturewas stirred under Hydrogen atmosphere for 2 hours. Then further PtO2(130 mg×3) was added and the reaction mixture was stirred under Hydrogenatmosphere for 13 hours overall. It was filtered over a celte pad andconcentrated in vacuo to a residue which was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound (610 mg) as ayellow oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.75 (detection with ninhydrine).

MS (ES/+): m/z=470 [M+Na]⁺.

Intermediate 44

3-(2,4-dichlorophenyl)-3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-4-piperidinyl)propanoicacid

A solution of lithium hydroxide monohydrate (285 mg) in water (4.5 mL)was added to a solution of intermediate 43 (610 mg) in MeOH (18.5 mL).The mixture was heated to 70° C. for 1 hour, then it was allowed to coolto r.t., diluted with AcOEt/H₂O, acidified to pH 4 with a pH3 buffersolution (citrate-hydrochloric acid buffer solution purchase from Fluka)and 1N hydrochloric acid solution. The aqueous layer was extracted withfurther AcOEt (3×100 mL). The organic extract was dried and concentratedin vacuo to give the title compound (574 mg) as a white solid.

MS (ES/−): m/z=418 [M−H]⁻.

Intermediate 45

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(2,4-dichlorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(45a) (Diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(2,4-dichlorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(45b) (diastereoisomer 2)

DIPEA (80 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (100 mg) were added to a solution of intermediate 44(95 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes,{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylamine (68 mg) wasadded. The mixture was stirred at r.t. overweekend, then it was dilutedwith water (5 mL) and extracted with AcOEt (10 mL). The organic layerwas dried, concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 8:2) to give:

-   intermediate 45a (51 mg) as a white foam;-   intermediate 45b (57 mg) as a white foam    Intermediate 45a

T.I.c.: CH/AcOEt 8:2, Rf=0.54.

NMR (d₁-CDCl₃): δ (ppm): 7.78 (s, 1H); 7.62 (s, 2H); 7.39 (s, 1H); 7.26(d, 1H); 7.18 (dd, 1H); 6.01 (q, 1H); 4.15 (dm, 1H); 4.02 (bm, 1H); 3.87(bm, 1H); 3.05 (dd, 1H); 2.92 (bm, 1H); 2.73 (dd, 1H); 2.65-2.75 (bm,1H); 2.68 (s, 3H); 1.94 (bm, 1H); 1.68 (m, 1H); 1.62 (m, 1H); 1.48 (m,1H); 1.43 (s, 9H); 1.37 (d, 3H).

Intermediate 45b

T.I.c.: CH/AcOEt 8:2, Rf=0.45.

MS (ES/+): m/z=695 [M+Na]⁺.

Intermediate 46

1,1-dimethylethyl4-[2-cyano-3-(ethyloxy)-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

A solution of 2-bromo, 5-fluorotoluene (2.26 mL) in anhydrous Et2O (6.5mL) was dropped into a suspension of magnesium turning (0.390 g) and fewcrystals of iodine in anhydrous Et2O (1.6 mL) under a Nitrogenatmosphere. The mixture refluxed for 30 minutes, then it was allowed tocool to r.t. 2.0 ml of this solution were added drop-wise tointermediate 19 (595 mg) in anhydrous Et2O (10 mL). At the end of theaddition the mixture was stirred for 2 hours at r.t. The mixture wasquenched with ammonium chloride saturated solution and extracted withAcOEt. The aqueous layer was extracted with further AcOEt. The combinedorganic extracts were dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (CH/AcOEt 8:2) to give the titlecompound (400 mg).

T.I.c.: CH/AcOEt 7:3, Rf=0.30 (detection with ninhydrine).

MS (ES/+): m/z=459 [M+Na]⁺.

Intermediate 47

1,1-dimethylethyl4-[2-cyano-1-(4-fluoro-2-methylphenyl)ethyl]-4-fluoro-1-piperidinecarboxylate

A mixture of intermediate 46 (165 mg), sodium chloride (9 mg) and water(15 μL) in anhydrous dimethylsulfoxide (2.5 mL) was heated to 160° C.for 2 hours. The mixture was allowed to cool to r.t., diluted with AcOEtand washed with water and brine. The aqueous layer was extracted withfurther AcOEt (3×20 mL). The organic layer was dried and concentrated invacuo. The residue was purified by flash chromatography (CH/AcOEt 80:20)to give the title compound (102 mg) as a colourless oil.

MS (ES/+): m/z=387 [M+Na]⁺.

Intermediate 48

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-4-piperidinyl)-3-(4-fluoro-2-methylphenyl)propanoicacid

A 3M potassium hydroxide solution (4.6 mL) was added to a solution ofintermediate 47 (99 mg) in abs. EtOH (4.6 mL). The mixture divided intotwo portions which were heated in microwave (300W, P=90 p.s.i.) at 150°C. for (10+10+10+5) minutes. Each solution was allowed to cool to r.t.,diluted with AcOEt/H₂O, acidified to pH 4/5 with a pH3 buffer solution(citrate-hydrochloric acid buffer solution purchase from Fluka) and 2Nhydrochloric acid solution. The aqueous layer was extracted with furtherAcOEt. The organic extract was dried and concentrated in vacuo to givethe title compound (58 mg) as a white solid.

MS (ES/−): m/z=382 [M−1]⁻.

Intermediate 49

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(49a) (diastereoisomer 1) (1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate(49b) (diastereoisomer 2)

DIPEA (37 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (57 mg) were added to a solution of intermediate 48(53 mg) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 15 minutes(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (45 mg) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith AcOEt (15 mL) and washed with water (3×15 mL). The organic layerwas dried, concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 95:5 to 75:25) to give:

-   intermediate 49a (23 mg) as colourless oil;-   intermediate 49b (36 mg) as colourless oil.    Intermediate 49a

T.I.c.: CH/AcOEt 1:1, Rf=0.80 (detection with ninhydrine).

MS (ES/+): m/z=659 [M+Na]⁺, 561 [M-tBu-F+H]⁺, 517 [M-BOC-F+H]⁺.

Intermediate 49b

T.I.c.: CH/AcOEt 1:1, Rf=0.64 (detection with ninhydrine).

MS (ES/+): m/z=659 [M+Na]⁺, 561 [M-tBu-F+H]⁺, 517 [M-BOC-F+H]⁺.

Intermediate 50

1,1-dimethylethyl4-[3-[[(3,5-dibromophenyl)methyl](methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

DIPEA (74 μL) and O-benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (58 mg) were added to a solution of intermediate 48(53 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 15 minutes intermediate[(3,5-dibromophenyl)methyl]methylamine (52 mg) was added. The mixturewas stirred at r.t. overnight, then it was diluted with AcOEt (15 mL)and washed with water (4×15 mL). The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 95:5 to 75:25) to give the title compound(38 mg) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.37 (detection with ninhydrine).

Intermediate 51

1,1-dimethylethyl4-[(3,4-dichlorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of 4-bromo-1,2-dichlorobenzene (2.44 mL) in anhydrous THF(2.5 mL) was dropped into a suspension of magnesium turning (0.444 mg)and few crystals of iodine in anhydrous THF (2.5 mL) under a Nitrogenatmosphere. The mixture was refluxed for 30 minutes and then cooled to0° C. A solution of intermediate 3 (1.5 g) in anhydrous THF (5.0 mL) wasdropped into the reaction mixture at 0° C. under a Nitrogen atmospherewhile stirring. At the end of the addition the mixture was allowed towarm to r.t. and stirred at 23° C. for 45 minutes. The mixture wasdiluted with DCM (20 mL), washed with a saturated ammonium chloridesolution (3×5 mL). The organic layer was dried and concentrated in vacuoto give 1,1-dimethylethyl4-[(3,4-dichlorophenyl)(hydroxy)methyl]-1-piperidinecarboxylate (1.43 g)

T.I.c.: CH/AcOEt 75:25, Rf=0.23).

This material was dissolved in anhydrous DCM (23 mL) and treatedportion-wise with Dess Martin periodinane (1.67 g) under a Nitrogenatmosphere. The brown solution was stirred at r.t. for 1.5 hours, thenthe solution was diluted with DCM (40 mL) and poured into a 5% solutionof sodium thiosulphate in saturated sodium hydrogen solution (100 mL).The mixture was stirred for 30 minutes, then the phases were separatedand the aqueous phase washed with DCM (2×10 mL). The collected organiclayers were dried and concentrated in vacuo to give the title compound(1.41 g) as a white solid.

T.I.c.: CH/AcOEt 75:25, Rf=0.32 (detection with ninhydrine).

Intermediate 52

1,1-dimethylethyl4-[(3,4-dichlorophenyl)carbonyl]-4-fluoro-1-piperidinecarboxylate

Lithium bis(trimethylsilyl)amide (1M in THF—6.30 mL) was added drop-wiseto a stirred solution of intermediate 51 (1.41 g) in anhydrous THF (72mL) previously cooled to −78° C. under a Nitrogen atmosphere. Afterstirring at −78° C. for 15 minutes and then at −10° C. for 1.5 hours,the mixture was cooled to −40° C. and a solution ofN-fluorobenzenesulfonimide (1.614 g) in anhydrous THF (15 mL) addeddrop-wise. The mixture was stirred at −40° C. for 30 minutes, thenallowed to reach r.t. and stirred at 23° C. for 75 minutes. The mixture,cooled to 0° C., was diluted AcOEt, washed with a saturated ammoniumchloride solution, the aqueous phase extracted with AcOEt and thecollected organic phases dried and concentrated in vacuo. The residuewas purified by flash chromatography (CH, CH/AcOEt from 95:5 to 80:20)to give the title compound (1.09 g) as a white solid.

T.I.c.: CH/AcOEt 75:25, Rf=0.52 (detection with ninhydrine).

MS (ES/+): m/z=396 [M+Na]⁺.

Intermediate 53

1,1-dimethylethyl4-[(1E)-1-(3,4-dichlorophenyl)-3-(ethyloxy)-3-oxo-1-propen-1-yl]-4-fluoro-1-piperidinecarboxylate

Triethylphosphonoacetate (2.37 mL) was added to a suspension of sodiumhydride (60% suspension in mineral oil—477.5 mg) in anhydrous THF (25mL) previously cooled to 0° C. under a Nitrogen atmosphere. The mixturewas allowed to warm to r.t. and stirred at 23° C. for 20 minutes. Then,a solution of intermediate 52 (1.123 g) in anhydrous THF (25 mL) wasadded drop-wise and the resulting solution was heated to reflux for 30minutes. The solution was allowed to cool to r.t., diluted with AcOEtand water. The aqueous phase was extracted with AcOEt, the collectedorganic phases washed with brine, dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH, CH/AcOEt from9:1 to 8:2) to give the title compound (1.28 g) as a white solid.

T.I.c.: CH/AcOEt 9:1, Rf=0.31 (detection with ninhydrine).

MS (ES/+): m/z=368 [M+Na]⁺.

Intermediate 54

1,1-dimethylethyl4-[1-(3,4-dichlorophenyl)-3-(ethyloxy)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

PtO2 (194 mg) was added to a solution of intermediate 53 (1.27 g) inabs. EtOH (100 mL) under a Nitrogen atmosphere. The reaction mixture wasstirred under Hydrogen atmosphere (1 atm) for 2 hours. The reactionmixture was filtered over a celite pad washing with MeOH andconcentrated in vacuo to give the title compound (1.28 g) as a yellowoil.

T.I.c.: CH/AcOEt 7:3, Rf=0.38 (detection with ninhydrine).

MS (ES/+): m/z=470 [M+Na]⁺.

Intermediate 55

3-(3,4-dichlorophenyl)-3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-4-piperidinyl)propanoicacid

A solution of lithium hydroxide monohydrate (597 mg) in water (8.5 mL)was added to a solution of intermediate 54 (1.27 g) in MeOH (34 mL). Themixture was heated to 80° C. for 1 hour, then it was allowed to cool tor.t., diluted with water and concentrated to half volume. The residuewas acidified with 3M hydrochloric acid solution and extracted withAcOEt. The organic layer was dried and concentrated in vacuo to give thetitle compound (1.204 g) as a white foam.

MS (ES/+): m/z=442 [M+Na]⁺.

Intermediate 56

1,1-dimethylethyl4-[3-[[(3,5-dibromophenyl)methyl](methyl)amino]-1-(3,4-dichlorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

DIPEA (124 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (99 mg) were added to a solution of intermediate 55(100 mg) in anhydrous DMF (6 mL) under a Nitrogen atmosphere. Afterstirring for 15 minutes intermediate[(3,5-dibromophenyl)methyl]methylamine (90 mg) was added. The mixturewas stirred at r.t. overnight, then it was diluted with AcOEt (20 mL)and washed with water (4×20 mL). The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 95:5 to 75:25) to give the title compound(135 mg) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.50 (detection with ninhydrine).

MS (ES/+): m/z=704 [M+Na]⁺; 605, 607 [M-tBu-F+H]⁺.

Intermediate 57

1,1-dimethylethyl4-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

DIPEA (0.430 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (339 mg) were added to a solution of intermediate 22(300 mg) in anhydrous DMF (10 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes,{[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine hydrochloride (286.1mg) was added. The mixture was stirred at r.t. for 2 days, then it wasdiluted with water (10 mL) and extracted with AcOEt (20 mL). The organiclayer was washed with brine (10 mL), dried, concentrated in vacuo andthe residue was purified by flash chromatography (CH/AcOEt 6:4) to givethe title compound (440 mg) as a yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.52 (detection with ninhydrine).

MS (ES/+): m/z=609 [M+H]⁺.

Intermediate 58

1,1-dimethylethyl4-[(4-chlorophenyl)(hydroxy)methyl]-1-piperidinecarboxylate

A solution of 4-chlorobromobenzene (2.47 mL) in anhydrous THF (5 mL) wasdropped into a suspension of magnesium turning (0.304 g) and fewcrystals of iodine in anhydrous THF (5 mL) under a Nitrogen atmosphere.The mixture refluxed for 30 minutes, then it was allowed to cool to r.t.and a mixture of intermediate 3 (1.0 g) in anhydrous THF (5 mL) wasadded drop-wise. At the end of the addition the mixture was allowed towarm to r.t. and stirred at 23° C. for 45 minutes. The mixture wasquenched with ammonium chloride saturated solution, stirred for 10minutes then extracted with DCM (3×50 mL). The combined organic extractswere concentrated in vacuo. The residue was purified by flashchromatography (CH/AcOEt 95:5 to 8:2) to give the title compound (1.33g) as a white foam.

T.I.c.: CH/AcOEt 75:25, Rf=0.31

MS (ES/+): m/z=326 [M+H]⁺.

Intermediate 59

1,1-dimethylethyl 4-[(4-chlorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of mixture of intermediate 58 (1.33 g) dissolved in anhydrousDCM (25 ml) was treated portion-wise with Dess Martin periodinane (1.74g) under a Nitrogen atmosphere. The brown solution was stirred at r.t.for 1.5 hours, then the solution was diluted with DCM (50 mL) and pouredinto a saturated sodium hydrogen carbonate solution (50 mL) containingsodium thiosulphate (2.5 g). The mixture was stirred for 30 minutes,then the phases were separated. The organic layer was washed with asaturated sodium hydrogen carbonate solution. The organic layer wasdried and concentrated in vacuo to give the title compound (1.18 g) as awhite solid.

T.I.c.: CH/AcOEt 75:25, Rf=0.5 (detection with ninhydrine).

MS (ES/+): m/z=324 [M+H]⁺.

Intermediate 60

1,1-dimethylethyl4-[(4-chlorophenyl)carbonyl]-4-fluoro-1-piperidinecarboxylate

A solution of Lithyum bis(trimethylsilyl)-amide (1M in THF—5.84 mL) wasdropped into a solution of intermediate 59 (1.18 g) dissolved inanhydrous THF (67 mL) previously cooled to −78° C. under a Nitrogenatmosphere. At the end of the addition the mixture was allowed to warmto 0° C. and stirred for 1.5 hours. Then the mixture was cooled to −40°C. and N-Fluorobenzene-sulfonimide (1.49 g) dissolved in anhydrous THF(14 mL) was added dropwise. Then the mixture was allowed to stirr tor.t. in about 2 hours and it was treated with ammonium chloridesaturated solution and extracted with AcOEt. The organic layer was driedand concentrated in vacuo to a residue which was purified by flashchromatography (CH/AcOEt 95:5 to 75:15) to give the title compound (1.14g).

T.I.c.: CH/AcOEt 7:3, Rf=0.66 (detection with ninhydrine).

MS (ES/+): m/z=286 [M-tBut+H]⁺.

Intermediate 61

1,1-dimethylethyl4-[1-(4-chlorophenyl)-3-(ethyloxy)-3-oxo-1-propen-1-yl]-4-fluoro-1-piperidinecarboxylate

Triethylphosphono Acetate (0.46 mL) was dropped into a sospension of NaH(60% in mineral oil, 0.093 g) in anhydrous THF (5 mL) previously cooledto 0° C. under a Nitrogen atmosphere. At the end of the addition themixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 60 (0.20 g) dissolved in anhydrous THF (5 mL) was added andthe mixture was stirred at reflux temperature. After 1 hour the mixturewas allowed to reach r.t. and was treated with water and extracted withEt2O. The organic layer was dried and concentrated in vacuo to a residuewhich was purified by flash chromatography (CH/AcOEt from 95:5 to 9:1)to give the title compound (0.21 g) as a mixture E/Z and as a whitesolid.

T.I.c.: CH/AcOEt 7:3, Rf=0.61 (detection with ninhydrine).

MS (ES/+): m/z=412 [M+H]⁺; 434 [M+Na]⁺.

Intermediate 62

1,1-dimethylethyl4-[1-(4-chlorophenyl)-3-(ethyloxy)-3-oxopropyl]-4-fluoro-1-piperidinecarboxylate

PtO₂ (35 mg) was added to a solution of intermediate 61 (210 mg) inanhydrous EtOH (20 mL) under an hydrogen pressure of 1 atmosphere for 3hours. Then, the reaction mixture was filtered over a celite pad washingwith MeOH and concentrated in vacuo to give the title compound (208 mg)as a colourless oil.

T.I.c.: CH/AcOEt 8:2, Rf=0.41 (detection with ninhydrine).

MS (ES/+): m/z=414 [M+H]⁺.

Intermediate 63

3-(4-chlorophenyl)-3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-4-piperidinyl)propanoicacid

A solution of lithium hydroxide monohydrate (0.6 g) in water (8.5 mL)was added to a solution of intermediate 62 (1.19 g) in MeOH (34 mL). Themixture was heated to 65° C. for 1 hour, then it was allowed to cool tor.t., acidified with 1M hydrochloric acid solution to pH 3 and extractedwith DCM (3×100 mL). The organic layer was washed with water, dried andconcentrated in vacuo to give the title compound (1.06 g) as a whitefoam.

MS (ES/+): m/z=408 [M+Na]⁺.

Intermediate 64

1,1-dimethylethyl4-{1-(4-chlorophenyl)-3-[[(3,5-dibromophenyl)methyl](methyl)amino]-3-oxopropyl}-4-fluoro-1-piperidinecarboxylate

DIPEA (136 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (108 mg) were added to a solution of intermediate 63(100 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 15 minutes intermediate[(3,5-dibromophenyl)methyl]methylamine (98 mg) was added. The mixturewas stirred at r.t. overnight, then it was diluted with AcOEt (15 mL)and washed with water (4×15 mL). The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 95:5 to 75:25) to give the title compound(120 mg) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.64 (detection with ninhydrine).

MS (ES/+): m/z=645 [M+H]⁺.

Intermediate 65

1-(1,1-dimethylethyl) 3-ethyl 1,3-piperidinedicarboxylate

TEA (10.4 ml) and a solution of di-tert-butyl-dicarbonate (6 g) inanhydrous DCM (10 mL) was added to a solution of ethyl3-piperidinecarboxylate (3.9 mL) in anhydrous DCM (50 mL) under aNitrogen atmosphere. The solution was stirred at r.t. for 4 hours, thenit was washed with brine, dried, concentrated in vacuo and the residuewas purified by flash chromatography (CH/AcOEt 9:1) to give the titlecompound (5.92 g) as a pale yellow oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.67 (detection with ninhydrine).

Intermediate 66

1,1-dimethylethyl 3-formyl-1-piperidinecarboxylate

Diisobutylaluminium hydride (1M in toluene—48.7 mL) was dropped into asolution of intermediate 65 (5.70 g) in anhydrous toluene (75 mL)previously cooled to −78° C. under a Nitrogen atmosphere. The solutionwas stirred at −78° C. for 2 hours, then it was quenched with a 10%sodium hydroxide solution (16 mL) at −78° C. The mixture was allowed towarm to r.t. and the layers were separated. The organic layer was washedwith a 10% sodium hydroxide solution and brine, dried, concentrated invacuo and the residue was purified by flash chromatography (CH/AcOEt9:1) to give the title compound (5 g) as colourless oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.35 (detection with ninhydrine).

MS (ES/+): m/z=236 [M+Na]⁺.

Intermediate 67a and 67b

1,1-dimethylethyl3-[(4-fluorophenyl)(hydroxy)methyl]-1-piperidinecarboxylate (67a)(diastereoisomer A) and 1,1-dimethylethyl3-[(4-fluorophenyl)(hydroxy)methyl]-1-piperidinecarboxylate (67b)(diastereoisomer B)

A solution of intermediate 66 (2.5 g) in anhydrous Et2O (50 mL) wasdropped into a solution of 4-fluorophenyl magnesium bromide (1M inTHF—35 mL) in anhydrous Et2O (35 mL) previously cooled to 0° C. under aNitrogen atmosphere. At the end of the addition the mixture was allowedto warm to r.t. and stirred at 23° C. for 30 minutes. The mixture wasquenched with a saturated ammonium chloride solution (50 mL). Theaqueous layer was further extracted with AcOEt. The combined organicextracts were washed with brine, dried and concentrated in vacuo to aresidue which was purified by flash chromatography (CH/AcOEt from 9:1 to7:3) to give a mixture of the title compounds as a yellow oil (2.5 g).Samples of few milligrams of single isomers from purification werecharacterised:

Intermediate 67a:

T.I.c.: CH/AcOEt 7:3, Rf=0.3

NMR (d₆-DMSO): δ (ppm): 7.31 (dd, 2H); 7.12 (t, 2H); 5.29 (d, 1H); 4.25(t, 1H); 4.05 (mb, 1H); 3.82 (d, 1H); 2.5 (m, 1H); 1.51-1.18 (m, 6H);1.34 (s, 9H).

MS (ES/+): m/z=310 [M+H]⁺.

Intermediate 67b:

T.I.c.: CH/AcOEt 7:3, Rf=0.28 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm): 7.30 (dd, 2H); 7.13 (t, 2H); 5.27 (d, 1H); 4.28(sb, 1H); 3.53 (mb, 1H); 3.77 (d, 1H); 2.60 (t, 1H); 1.85 (sb, 1H);1.61-1.22 (m, 5H); 1.29 (s, 9H).

MS (ES/+): m/z=310 [M+H]⁺.

Intermediate 68

1,1-dimethylethyl 3-[(4-fluorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of mixture of intermediate 67a and 67b (0.1 g) was dissolvedin anhydrous DCM (2 mL) and treated portion-wise with Dess Martinperiodinane (0.14 g) under a Nitrogen atmosphere. The brown solution wasstirred at r.t. for 3 hours, then the solution was diluted with DCM (5mL) and poured into a saturated sodium hydrogen carbonate solution (7mL) containing sodium thiosulphate (0.35 g). The mixture was stirred for30 minutes, then the phases were separated. The organic layer was washedwith a saturated sodium hydrogen carbonate solution. The organic layerwas dried and concentrated in vacuo to a residue which was purified byflash chromatography (CH/AcOEt from 9:1 to 8:2) to give the titlecompound (0.073 g) as a white solid.

T.I.c.: CH/AcOEt 7:3, Rf=0.5 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm) 8.02 (dd, 2H); 7.16 (t, 2H); 4.27 (sb, 1H); 4.11(db, 1H); 3.37 (t, 1H); 2.94 (sb, 1H); 2.77 (t, 1H); 2.03 (d, 1H); 1.78(m, 1H); 1.71 (dd, 1H); 1.6 (m, 1H); 1.48 (s, 9H).

MS (ES/+): m/z=308 [M+H]⁺.

Intermediate 69

1,1-dimethylethyl3-fluoro-3-[(4-fluorophenyl)carbonyl]-1-piperidinecarboxylate

A solution of Lithyum bis(trimethylsilyl)-amide (1M in THF—2.6 mL) wasdropped into a solution of intermediate 68 (0.5 g) dissolved inanhydrous THF (30 mL) previously cooled to −78° C. under a Nitrogenatmosphere. At the end of the addition the mixture was allowed to warmto −10° C. and stirred for 1 hour. Then the mixture was cooled to −40°C. and N-Fluorobenzene-sulfonimide (0.668 g) dissolved in anhydrous THF(6 mL) was added. The mixture was stirred for 1 hour then furtherN-Fluorobenzene-sulfonimide (0.050 g) was added and the mixture wasallowed to stirr to r.t. then it was treated with ammonium chloridesaturated solution (50 mL). The mixture was stirred at r.t. for 10minutes, then a white precipitated was formed. The precipitate wasfiltered off and the mixture was extracted with AcOEt. The organic layerwas dried and concentrated in vacuo to a residue which was purified byflash chromatography (CH/AcOEt 9:1) to give the title compound (0.38 g).

T.I.c.: CH/AcOEt 7:3, Rf=0.6 (detection with ninhydrine).

NMR (CDCl3): δ (ppm) 8.15 (t, 2H); 7.14 (t, 2H); 4.35 (m, 2H); 3.35 (m,1H); 2.85 (s, 1H); 2.1 (m, 3H); 1.68 (d, 1H); 1.48 (s, 9H).

MS (ES/+): m/z=326 [M+H]⁺.

Intermediate 70

1,1-dimethylethyl3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-3-fluoro-1-piperidinecarboxylate

Triethylphosphono Acetate (0.93 mL) was dropped into a sospension of NaH(60% in mineral oil, 0.112 g) in anhydrous THF (10 mL) previously cooledto 0° C. under a Nitrogen atmosphere. At the end of the addition themixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 69 (0.38 g) dissolved in anhydrous THF (10 mL) was addedand the mixture was stirred at reflux temperature. After 2 hours themixture was allowed to reach r.t. and was treated with water andextracted with Et2O. The organic layer was dried and concentrated invacuo to a residue which was purified by flash chromatography (CH/AcOEt(9:1) to give the title compound (0.45 g) as a yellow oil.

T.I.c.: CH/AcOEt 8:2, Rf=0.42 (detection with ninhydrine).

NMR (CD3OD): δ (ppm) 7.13 (m, 4H); 6.33 (s, 1H); 4.14 (t, 1H); 3.98 (d,1H); 3.93 (q, 2H); 3.07 (dd, 1H); 2.72 (t, 1H); 2.05-1.75 (m, 3H); 1.56(m, 1H); 1.43 (s, 9H); 1.01 (t, 3H).

MS (ES/+): m/z=396 [M+H]⁺.

Intermediate 71

1,1-dimethylethyl-3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate(71a) and1,1-dimethylethyl-3-[1-(4-fluorophenyl)-3-(methyloxy)-3-oxopropylidene]-1-piperidinecarboxylate(71b)

Magnesium turnings (12 mg) were added to a solution of intermediate 70(38 mg) in anhydrous MeOH (1 mL) under a Nitrogen atmosphere with a lowheating until hydrogen evolution is observed. The reaction mixture wasstirred at r.t. overnight, then water (2 mL) and ammonium chloridesaturated solution were added and the mixture was extracted with AcOEt.The organic phase was dried and concentrated in vacuo to give a mixtureof title compounds (33 mg) as a colourless oil.

Intermediate 71a:

MS (ES/+): m/z=400 [M+Na]⁺.

Intermediate 71b:

MS (ES/+): m/z=386 [M+Na]⁺.

Intermediate 72

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-piperidinylidene)-3-(4-fluorophenyl)propanoicacid

A solution of lithium hydroxide monohydrate (17 mg) in water (0.25 mL)was added to a solution of intermediate 71a and 71b (33 mg) in MeOH (1.0mL). The mixture was heated to 65° C. for 1 hour, then it was allowed tocool to r.t., acidified to ph=3 with 1M hydrochloric acid solution andextracted with AcOEt. The organic layer was washed with water, dried andconcentrated in vacuo to give the title compound (30 mg) as a yellowoil.

T.I.c.: CH/AcOEt 1:1, Rf 0.18 (detection with ninhydrine).

MS (ES/−): m/z=348 [M−H]⁻.

Intermediate 73

1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate(73a) (isomer 1) 1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate(73b) (isomer 2)

DIPEA (0.044 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.034 g) were added to a solution of intermediate 72(0.03 g) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes, (3,5-bis-trifluoromethyl-benzyl)-methylaminehydrochloride (0.028 g) was added. The mixture was stirred at r.t.overnight, then it was diluted with AcOEt and washed with cold water.The organic layer was dried, concentrated in vacuo to a residue that waspurified by flash chromatography (CH/AcOEt 9:1) to give:

-   intermediate 73a (8 mg) as yellow oil;-   intermediate 73b (14 mg) as yellow oil.    Intermediate 73a

T.I.c.: CH/AcOEt 1:1, Rf=0.7.

NMR (CDCl3): δ (ppm) 7.78 (s, 1H); 7.61 (s, 2H); 7.11 (t, 2H); 6.98 (t,2H); 4.60 (s, 2H); 4.13 (s, 2H); 3.61 (s, 2H); 3.49 (s, 2H); 2.90 (s,3H); 2.20 (t, 2H); 1.5 (m, 2H); 1.48 (s, 9H).

MS (ES/+): m/z=589 [M+H]⁺.

intermediate 73b

T.I.c.: CH/AcOEt 1:1, Rf=0.4.

NMR (CDCl3): δ (ppm) 7.79 (s, 1H); 7.60 (s, 2H); 7.13 (t, 2H); 6.99 (t,2H); 4.60 (s, 2H); 3.87 (s, 2H); 3.51 (m, 4H); 2.85 (s, 3H); 2.46 (t,2H); 1.73 (sb, 2H); 1.28 (db, 9H).

MS (ES/+): m/z=589 [M+H]⁺.

Intermediate 74

1,1-dimethylethyl 3-formyl-1-pyrrolidinecarboxylate

Dimethylsulfoxide (0.106 mL) dissolved in anhydrous DCM (2 mL) was addedto a solution of oxalyl chloride (0.065 mL) in anhydrous DCM (1 mL)previously cooled to −78° C. under a Nitrogen atmosphere. The solutionwas stirred at −78° C. for 15 minutes, then a solution of1,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.075 g)in anhydrous DCM (2 mL) was slowly added. The mixture was allow to warmto −30° C. in 2 hours, then TEA (0.312 mL) was added. The mixture wasallowed to warm to r.t. over 1 hour, then it was diluted with DCM andwashed with water. The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (DCM/MeOH from98:2 to 96:4) to give the title compound (0.065 g).

T.I.c.: DCM/MeOH 9:1, Rf=0.5.

MS (ES/+): m/z=200 [M+H]⁺.

Intermediate 75

1,1-dimethylethyl3-[(4-fluorophenyl)(hydroxy)methyl]-1-pyrrolidinecarboxylate

A solution of intermediate 74 (0.100 g) in anhydrous Et2O (2 mL) wasdropped into a solution of 4-fluorophenyl magnesium bromide (1M in THF−1.5 mL) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. At the end of the addition the mixture was allowedto warm to r.t. and stirred at 23° C. for 30 minutes. The mixture wasquenched with a saturated ammonium chloride solution (1 mL). The aqueouslayer was further extracted with AcOEt. The combined organic extractswere washed with brine, dried and concentrated in vacuo to give aresidue which was purified by flash chromatography (DCM/MeOH 98:2) togive the title compound (0.162 g) as diastereomeric mixture.

T.I.c.: DCM/MeOH 9:1, Rf=0.65

NMR (d₆-DMSO): δ (ppm): 7.36 (m, 2H); 7.13 (t, 2H); 5.41 (dd, 1H); 4.41(m, 1H); 3.3 (m, 2H); 3.1 (m, 1H); 2.9 (m, 1H); 2.3 (m, 1H); 1.8 (m,2H); 1.36 (d, 9H).

MS (ES/+): m/z=296 [M+H]⁺.

Intermediate 76

1,1-dimethylethyl 3-[(4-fluorophenyl)carbonyl]-1-pyrrolidinecarboxylate

A solution of mixture of intermediate 75 (0.160 g) was dissolved inanhydrous DCM (3 mL) and treated portion-wise with Dess Martinperiodinane (0.232 g) under a Nitrogen atmosphere. The brown solutionwas stirred at r.t. for 3 hours, then the solution was diluted with DCM(5 mL) and poured into a saturated sodium hydrogen carbonate solution (7mL) containing sodium thiosulphate (0.3 g). The mixture was stirred for30 minutes, then the phases were separated. The organic layer was washedwith a saturated sodium hydrogen carbonate solution. The organic layerwas dried and concentrated in vacuo to a residue which was purified byflash chromatography (DCM/MeOH (98:2) to give the title compound (0.100g) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.09 (dd, 2H); 7.37 (t, 2H); 4.17 (m, 1H); 3.52(dd, 1H); 3.42 (dd, 1H); 2.5 (mb, 2H); 2.16 (m, 1H); 1.95 (m, 1H); 1.39(s, 9H).

MS (ES/+): m/z=294 [M+H]⁺.

Intermediate 77

1,1-dimethylethyl3-fluoro-3-[(4-fluorophenyl)carbonyl]-1-pyrrolidinecarboxylate

A solution of Lithyum bis(trimethylsilyl)-amide (1M in THF—0.287 mL) wasdropped into a solution of intermediate 76 (0.056 g) dissolved inanhydrous THF (3 mL) previously cooled to −78° C. under a Nitrogenatmosphere. At the end of the addition the mixture was allowed to warmto 0° C. and stirred for 1.5 hours. Then the mixture was cooled to −40°C. and N-Fluorobenzene-sulfonimide (0.072 g) dissolved in anhydrous THF(0.6 mL) was added. Then the mixture was allowed to stirr to r.t. inabout 3.5 hours and it was treated with ammonium chloride saturatedsolution and extracted with AcOEt. The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (CH/AcOEt from 9:1 to 7:3) to give the title compound(0.013 g) as a yellow oil.

T.I.c.: CH/AcOEt 7:3, Rf=0.57 (detection with ninhydrine).

NMR (d₆-DMSO, 60° C.): δ (ppm) 8.1-8.02 (m, 2H); 7.4-7.3 (t, 2H); 3.89(s, 1H); 3.80 (s, 1H); 3.66 (m, 1H); 3.40 (m, 1H); 2.6-2.4 (m, 2H); 1.4(s, 9H).

MS (ES/+): m/z=312 [M+H]⁺; 334 [M+Na]⁺.

Intermediate 78

1,1-dimethylethyl3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-3-fluoro-1-pyrrolidinecarboxylate

Triethyl phosphonoacetate (0.135 mL) was dropped into a suspension ofNaH (60% in mineral oil, 0.027 g) in anhydrous THF (2 mL) previouslycooled to 0° C. under a Nitrogen atmosphere. At the end of the additionthe mixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 77 (0.05 g) dissolved in anhydrous THF (2 mL) was added andthe mixture was stirred at reflux temperature. After 1 hours the mixturewas allowed to reach r.t and was treated with water and extracted withEt2O. The organic layer was dried and concentrated in vacuo to a residuewhich was purified by flash chromatography (CH/AcOEt 9:1) to give thetitle compound (0.057 g) as a thick colourless oil.

T.I.c.: CH/AcOEt 9:1, Rf=0.23 (detection with ninhydrine).

MS (ES/+): m/z=382 [M+H]⁺.

Intermediate 79

1,1-dimethylethyl-3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropylidene]-1-pyrrolidinecarboxylate

Magnesium turnings (18 mg) were added to a solution of intermediate 78(55 mg) in anhydrous MeOH (1 mL) under a Nitrogen atmosphere with a lowheating until hydrogen evolution is observed. Then, the reaction mixturewas stirred at r.t. overnight, then water (2 mL) and ammonium chloridesolution were added and extracted with AcOEt. The organic phase wasdried and concentrated in vacuo to give the title compound (50 mg) as acolourless oil.

MS (ES/+): m/z=386 [M+Na]⁺.

T.I.c.: CH/AcOEt 7:3, Rf=0.6(detection with ninhydrine).

Intermediate 80

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinylidene)-3-(4-fluorophenyl)propanoicacid

Intermediate 79 (50 mg) was dissolved in MeOH (1 mL), treated with asolution of lithium hydroxide monohydrate (29 mg) in water (0.25 mL).The mixture was heated to 65° C. for 1 hour, then it was allowed to coolto r.t., acidified to pH 3 with 1M hydrochloric acid solution andextracted with AcOEt. The organic layer was washed with water, dried andconcentrated in vacuo to give the title compound (40 mg) as a whitefoam.

T.I.c.: CH/AcOEt 1:1, Rf 0.18 (detection with ninhydrine).

MS (ES/−): m/z=334 [M−H]⁻.

Intermediate 81

1,1-dimethylethyl(3E)-3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-pyrrolidinecarboxylate(81a) and 1,1-dimethylethyl(3Z)-3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-pyrrolidinecarboxylate(81b) DIPEA (0.08 mL) andO-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(0.062 g) were added to a solution of intermediate 80 (0.04 g) inanhydrous DMF (4 mL) under a Nitrogen atmosphere. After stirring for 20minutes, (3,5-bis-trifluoromethyl-benzyl)-methyl-amine hydrochloride(0.039 g) was added. The mixture was stirred at r.t. overnight, then itwas taken up with AcOEt (30 mL) and washed with water (4×5 mL) and brine(2×5 mL). The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH/AcOEt 7/3) to give thetitle compounds:

-   Intermediate 81a (0.023 g) as a white foam;-   Intermediate 81b (0.025 g) as a white foam.    Intermediate 81a

T.I.c.: CH/AcOEt 1:1, Rf=0.4 (detection with ninhydrine).

MS (ES/+): m/z=597 [M+Na]⁺

Intermediate 81b

T.I.c.: CH/AcOEt 1:1, Rf=0.2 (detection with ninhydrine).

MS (ES/+): m/z=597 [M+Na]⁺

Intermediate 82

1,1-dimethylethyl4-[3-ethyloxy)-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate

Magnesium turnings (70 mg) were added to a solution of intermediate 36(200 mg) in anhydrous MeOH (1 mL) under a Nitrogen atmosphere with a lowheating until hydrogen evolution is observed. Then, the reaction mixturewas stirred at r.t. for 6 h, then water (10 ml mL) and ammonium chloridesolution were added and extracted with AcOEt (2×10 mL). The organicphase was dried and concentrated in vacuo; the crude was purified byflash chromatography (CH/AcOEt 8:2) to give the title compound (180 mg)of colourless oil.

T.I.c.: CH/AcOEt=7:3, Rf 0.64 (detection with ninhydrine).

MS (ES/+): m/z=378 [M+H]⁺.

Intermediate 83

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinylidene)-3-(4-fluorophenyl)propanoicacid

Intermediate 82 was dissolved in MeOH (5 mL), treated with a solution ofLithium hydroxide monohydrate (100 mg) in water (1.25 mL). The mixturewas heated to 70° C. for 2 hour, then it was allowed to cool to r.t.,acidified to pH 3 with 1M Hydrochloric acid solution and extracted withAcOEt (2×15 mL). The organic layer was washed with water, dried andconcentrated in vacuo to give the title compound (150 mg) as a whitefoam.

T.I.c.: CH/AcOEt 1:1, Rf 0.20 (detection with ninhydrine).

MS (ES/+): m/z=350 [M+H]⁺.

Intermediate 84

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate

DIPEA (0.023 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.036 g) were added to a solution of intermediate 83(0.03 g) in anhydrous DMF (2 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes,{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylamine (0.021 g) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith AcOEt and washed with water. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 8:2 to 7:3) to give the title compound(40.5 mg) as yellow oil.

MS (ES/+): m/z=589 [M+H]⁺.

Intermediate 85

1,1-dimethylethyl4-[3-[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate

DIPEA (0.023 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.036 g) were added to a solution of intermediate 83(0.03 g) in anhydrous DMF (2 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ehtyl]-methyl-amine (0.021 g)was added. The mixture was stirred at r.t. overnight, then it wasdiluted with AcOEt and washed with water. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 8:2 to 7:3) to give the title compound (40mg) as yellow oil.

MS (ES/+): m/z=589 [M+H]⁺.

Intermediate 86

1,1-dimethylethyl4-[3-[[(3,5-dibromophenyl)methyl](methyl)amino]-1-(4-fluorophenyl)-3-oxopropylidene]-1-piperidinecarboxylate

DIPEA (0.046 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.036 g) were added to a solution of intermediate 83(0.03 g) in anhydrous DMF (2 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes (3,5-bis-bromo-benzyl)-methylamine hydrochloride(0.025 g) was added. The mixture was stirred at r.t. overnight, then itwas diluted with AcOEt and washed with water. The organic layer wasdried, concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt from 95:5 to 7:3) to give the title compound(44 mg) as yellow oil;

MS (ES/+): m/z=609 [M+H]⁺.

T.I.c.: CH:AcOEt=1:1 Rf 0.65 (detection with ninhydrine).

Intermediate 87

1,1-dimethylethyl4-[2-cyano-3-(ethyloxy)-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-3,6-dihydro-1(2H)-pyridinecarboxylate

A solution of 2-bromo, 5-fluorotoluene (2.06 mL) in anhydrous Et2O (6.5mL) was dropped into a suspension of magnesium turning (0.396 g) and fewcrystals of iodine in anhydrous Et2O (1.6 mL) under a Nitrogenatmosphere. The mixture refluxed for 30 minutes, then it was allowed tocool to r.t. 3.1 ml of this solution were added dropwise to intermediate19 (665 mg) in anhydrous Et2O (10 mL). At the end of the addition themixture was heated to reflux and stirred for 1 hour. The mixture wasquenched with ammonium chloride saturated solution and extracted withAcOEt. The aqueous layer was extracted with further AcOEt. The combinedorganic extracts were dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (CH/AcOEt from 9:1 to 8:2) to givethe title compound (300 mg).

TIc: CH/AcOEt 7:3, Rf=0.34 (detection with ninhydrine).

MS (ES/+): m/z=439 [M+Na]⁺.

Intermediate 88

1,1-dimethylethyl4-[2-cyano-1-(4-fluoro-2-methylphenyl)ethyl]-3,6-dihydro-1(2H)-pyridinecarboxylate

A mixture of intermediate 87 (300 mg), sodium chloride (14 mg) and water(28 μL) in anhydrous dimethylsulfoxide (3 mL) was heated to 160° C. for2 hours. The mixture was allowed to cool to r.t., diluted with AcOEt andwashed with water and brine. The aqueous layer was extracted withfurther AcOEt (3×20 mL). The organic layer was dried and concentrated invacuo. The residue was purified by silica cartridge (CH/AcOEt from 98/2to 80:20) to give the title compound (210 mg) as a colourless oil.

MS (ES/+): m/z=367 [M+Na]⁺.

Intermediate 89

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-1,2,3,6-tetrahydro-4-pyridinyl)-3-(4-fluoro-2-methylphenyl)propanoicacid

(GSK 232254A-VDLU/6207/62/2)

A 3M potassium hydroxide solution (9 mL) was added to a solution ofintermediate 88 (210 mg) in abs. EtOH (9 mL). The mixture divided intothree portions which were heated in microwave (300W, P=90 p.s.i.) at150° C. for (10+10+10) minutes. Each solution was allowed to cool tor.t., diluted with AcOEt/H₂O, acidified to pH 4/5 with a pH3 buffersolution (citrate-hydrochloric acid buffer solution purchase from Fluka)and 2N hydrochloric acid solution. The aqueous layer was extracted withfurther AcOEt (3×10 mL). The organic extract was dried and concentratedin vacuo to give the title compound (154 mg) as a white solid.

TIc: AcOEt, Rf=0.44 (detection with ninidrina).

NMR (d₁-CDCl3): δ (ppm) 7.06 (t, 1H); 6.87 (d, 2H); 5.50 (bs, 1H);3.98-3.29 (m, 5H); 2.78 (dd, 2H); 6.08 (q, 1H); 2.36 (s, 3H); 1.45 (s,9H).

Intermediate 90

1,1-dimethylethyl4-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-3,6-dihydro-1(2H)-pyridinecarboxylate

DIPEA (65 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (52 mg) were added to a solution of intermediate 89(46 mg) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes,{[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine hydrochloride (41mg) was added. The mixture was stirred at r.t. overnight, then it wasdiluted with water (5 mL) and extracted with AcOEt (20 mL). The organiclayer was dried, concentrated in vacuo and the residue was purified byflash chromatography (CH/AcOEt 7:3) to give the title compound (44 mg)as a white foam.

T.I.c.: CH/AcOEt 6:4, Rf=0.41.

MS (ES/+): m/z=367 [M+Na]⁺.

Intermediate 91

1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(91a) (diastereoisomer 1) and 1,1-dimethylethyl4-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluoro-2-methylphenyl)-3-oxopropyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(91b) (diastereoisomer 2)

DIPEA (42 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (67 mg) were added to a solution of intermediate 89(60 mg) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes,{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylamine (46.7 mg) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith water (5 mL) and extracted with AcOEt (20 mL). The organic layerwas dried, concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 7:3) to give:

-   intermediate 91a (25.5 mg) as a white foam;-   intermediate 91 b (20.2 mg) as a white foam.    Intermediate 91a

T.I.c.: CH/AcOEt 7:3, Rf=0.73.

NMR (d₁-CDCl3): δ (ppm) 7.80 (s, 1H); 7.66 (s, 2H); 7.05 (dd, 1H); 6.87(dd, 1H); 6.84 (d, 1H); 6.08 (q, 1H); 5.39 (b, 1H); 4.21 (t, 1H); 3.92(bs, 2H); 3.50 (dd, 1H); 3.31 (dd, 1H); 2.84 (dd, 1H); 2.78 (dd, 1H);2.61 (s, 3H); 2.40 (s, 3H); 2.01 (s, 2H); 1.45 (b, 9H); 1.41 (d, 3H).

Intermediate 91b

T.I.c.: CH/AcOEt 7:3, Rf=0.63.

NMR (d₁-CDCl3): δ (ppm) 7.73 (s, 1H); 7.50 (s, 2H); 6.98 (dd, 1H); 6.81(dd, 1H); 6.80 (d, 1H); 6.02 (q, 1H); 5.36 (b, 1H); 4.16 (t, 1H); 3.88(bs, 2H); 3.44 (dd, 1H); 3.29 (dd, 1H); 2.77 (dd, 1H); 2.61 (dd, 1H);2.62 (s, 3H); 2.34 (s, 3H); 1.96 (b, 2H); 1.49 (d, 3H); 1.42 (s, 9H).

Intermediate 92

1,1-dimethylethyl3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-1-pyrrolidinecarboxylate

Pd/C (10%, 10 mg) was added to a solution of intermediate 78 (65 mg) inanhydrous EtOH (8 mL) under a hydrogen pressure of 3.5 atmospheres andreacted overnight. Then, the reaction mixture was filtered over a Celitepad washing with MeOH/DCM and concentrated in vacuo to give the titlecompound (45 mg) as a yellow oil:

T.I.c.: CH/AcOEt 7:3, Rf=0.44.

MS (ES/+): m/z=388 [M+Na]⁺.

Intermediate 93

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)-3-(4-fluorophenyl)propanoicacid

Intermediate 92 (45 mg) was dissolved in MeOH (2 mL), treated with asolution of lithium hydroxide monohydrate (25 mg) in water (0.5 mL). Themixture was heated to 65° C. for 1 hour, then it was allowed to cool tor.t., acidified to pH 3 with 1M hydrochloric acid solution and extractedwith AcOEt. The organic layer was washed with water, dried andconcentrated in vacuo to give the title compound (44 mg) as a whitefoam.

T.I.c.: CH/AcOEt 1:1, Rf 0.2 (detection with ninhydrine).

MS (ES/−): m/z=336 [M−H]⁻.

Intermediate 94

1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-pyrrolidinecarboxylate(94a) (diastereoisomer A) 1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-pyrrolidinecarboxylate(94b) (diastereoisomer B)

DIPEA (0.065 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.052 g) were added to a solution of intermediate 93(0.044 g) in anhydrous DMF (4 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes,{[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine hydrochloride (0.045g) was added. The mixture was stirred at r.t. overnight, then it wastaken up with AcOEt (30 mL) and washed with water (4×5 mL) and brine(2×5 mL). The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH/AcOEt 8/2) to give:

-   intermediate 94a (20 mg) as a white foam;-   intermediate 94b (20 mg) as a white foam.    Intermediate 94a

T.I.c.: CH/AcOEt 7:3, Rf=0.35 (detection with ninhydrine).

MS (ES/+): m/z=599 [M+Na]⁺.

Intermediate 94b

T.I.c.: CH/AcOEt 7:3, Rf=0.28 (detection with ninhydrine).

MS (ES/+): m/z=599 [M+Na]⁺.

Intermediate 95

1,1-dimethylethyl3-[3-ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-3-fluoro-1-piperidinecarboxylate

Pd/C (10%, 5 mg) was added to a solution of intermediate 70 (50 mg) inanhydrous EtOH (4 mL) under an hydrogen pressure of 1.5 atmosphereovernight. Then, the reaction mixture was filtered over a celite padwashing with MeOH/DCM and concentrated in vacuo to give the titlecompound (50 mg) as a yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.8 (detection with ninhydrine).

MS (ES/+): m/z=420 [M+Na]⁺.

Intermediate 96

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-3-piperidinyl)-3-(4-fluorophenyl)propanoicacid

A solution of lithium hydroxide monohydrate (26 mg) in water (0.4 mL)was added to a solution of intermediate 95 (50 mg) in MeOH (1.6 mL). Themixture was heated to 65° C. for 1 hour, then it was allowed to cool tor.t., acidified with 1M hydrochloric acid solution and extracted withDCM. The organic layer was washed with water, dried and concentrated invacuo to give the title compound (47 mg) as a yellow oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.4, Rf=0.2 (detection with ninhydrine).

MS (ES/−): m/z=368 [M−H]⁻.

Intermediate 97

1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-3-fluoro-1-piperidinecarboxylate(97a) (diastereoisomer A) 1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-3-fluoro-1-piperidinecarboxylate(97b) (diastereoisomer B)

DIPEA (0.067 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.053 g) were added to a solution of intermediate 96(0.047 g) in anhydrous DMF (6 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes, (3,5-bis-trifluoromethyl-benzyl)-methylaminehydrochloride (0.045 g) was added. The mixture was stirred at r.t.overnight, then it was diluted with AcOEt and washed with cold water.The organic layer was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt from 9:1 to 6:4) to give:

-   intermediate 97a (19 mg) as yellow oil;-   intermediate 97b (38 mg) as yellow oil.    Intermediate 97a

T.I.c.: CH/AcOEt 6:4, Rf=0.46

MS (ES/+): m/z=609 [M+H]⁺

Intermediate 97b

T.I.c.: CH/AcOEt 6:4, Rf=0.25

MS (ES/+): m/z=609 [M+H]⁺.

Intermediate 98

1,1-dimethylethyl-2-[(4-fluorophenyl)(hydroxy)methyl]-4-morpholinecarboxylate

A solution of 4-fluorophenyl magnesium bromide (1M in THF—0.460 mL) inanhydrous Et2O (0.5 mL) was dropped into a solution of 1,1-dimethylethyl2-formyl-4-morpholinecarboxylate (0.05 g) in anhydrous Et2O (1 mL)previously cooled to 0° C. under a Nitrogen atmosphere. The mixture wasallowed to warm to r.t. and stirred for 45 minutes then treated withsaturated ammonium chloride solution (1 mL). The mixture was stirred atr.t. for 30 minutes, then Et2O was added and the layers were separated.The aqueous layer was extracted with further Et2O. The combined organicextracts were washed with a saturated sodium hydrogen carbonate andbrine, then dried and concentrated in vacuo. The residue was purified byflash chromatography (DCM, DCM from 95:5 to 8:2) to give the titlecompound (0.044 g) as a white foam.

T.I.c.: CH2Cl2/AcOEt 9:1, Rf=0.29.

NMR (CDCl3): δ (ppm) 7.30 (dd, 2H), 7.00 (t, 2H), 4.55 (d, 1H), 4.00 (d,1H), 3.80 (bd, 1H), 3.55 (m, 2H), 3.40 (m, 1H), 3.05-2.85 (m, 2H), 2.65(bs, 1H), 1.45 (s, 9H).

Intermediate 99

1,1-dimethylethyl 2-[(4-fluorophenyl)carbonyl]-4-morpholinecarboxylate

To a solution of intermediate 98 (200 mg) in anhydrous DCM (5 mL)Dess-Martin periodinane (272 mg) was added portionwise within 2 hours atr.t. under a Nitrogen atmosphere. The mixture was stirred at r.t. for 30minutes, then a solution of Na₂S₂O₃ (5% in saturated aqueous solution ofNaHCO₃, 4 ml) was added. After stirring for 1 hour the mixture wasextracted with DCM, the combined organic extracts were washed with asaturated sodium hydrogen carbonate and brine then dried andconcentrated in vacuo. The residue was purified by flash chromatography(from DCM, DCM from 95:5 to 9:1) to give the title compound (135 mg).

T.I.c.: CH2Cl2/AcOEt 9:1, Rf=0.65.

NMR (CDCl3): δ (ppm): 8.03 (dd, 2H), 7.13 (t, 2H), 4.65 (bd, 1H), 4.20(bs, 1H), 4.01 (m, 1H), 3.89 (bd, 1H), 3.68 (m, 1H), 3.07 (m, 2H), 1.46(s, 9H).

MS (ES/+): m/z=332 [M+Na]⁺.

Intermediate 100

1,1-dimethylethyl2-[(1Z)-3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-4-morpholinecarboxylate(100a) 1,1-dimethylethyl2-[(1E)-3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-4-morpholinecarboxylate(100b)

Triethylphosphonoacetate (350 μL) was added to a suspension of sodiumhydride (65% suspension in mineral oil—65 mg) in anhydrous THF (5 mL)previously cooled to 0° C. under a Nitrogen atmosphere. The mixture wasallowed to warm to r.t. and stirred at 23° C. for 20 minutes. Then, asolution of intermediate 99 (135 mg) in anhydrous THF (5 mL) was addedand the resulting solution was heated to reflux for 1.5 hours. Thesolution was allowed to cool to r.t., diluted with water and extractedwith Et2O. The organic layer was washed with water and brine, dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (CH, CH/AcOEt from 95:5 to CH/AcoEt 9:1) to give:

-   intermediate 99a (35 mg) as oil;-   intermediate 99b (51 mg) as oil.    Intermediate 100a:

T.I.c.: CH/AcOEt 8:2, Rf=0.40.

NMR (CDCl3): δ (ppm): 7.42 (dd, 2H), 7.00 (t, 2H), 5.92 (s, 1H), 5.36(dd, 1H), 4.20 (q, 2H), 4.02 (d, 2H), 3.90 (dd, 1H), 4.05-3.75 (broad,1H), 3.61 (m, 1H), 2.88 (m, 2H), 1.44 (s, 9H), 1.30 (t, 3H).

MS (ES/+): m/z=402 [M+Na]⁺.

Intermediate 100b:

T.I.c.: CH/AcOEt 8:2, Rf=0.31.

NMR (CDCl3): δ (ppm): 7.13 (dd, 2H), 7.03 (t, 2H), 6.24 (d, 1H), 4.06(d, 1H), 4.05-3.95 (m, 1H), 3.98 (q, 2H), 3.90-3.75 (bs, 2H), 3.59 (m,1H), 2.92 (m, 1H), 2.55 (m, 1H), 1.37 (s, 9H), 1.08 (t, 3H).

MS (ES/+): m/z=402 [M+Na]⁺.

Intermediate 101

1,1-dimethylethyl2-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-4-morpholinecarboxylate(101a) (diastereoisomer A) and 1,1-dimethylethyl2-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-4-morpholinecarboxylate(101b) (diastereoisomer B)

To a solution of a mixture of intermediate 100a and 100b (115 mg) inanhydrous MeOH (10 mL) Palladium (10% wt on carbon powder, 34 mg) wasadded. The mixture was saturated with hydrogen (4 atm) and stirred atr.t. for 3.5 hours. After filtration of the catalyst and evaporation ofthe solvent, the residue was purified by flash chromatography (CH,CH/AcOEt from 95:5 to 9:1) to give:

-   intermediate 101a (38 mg) as an oil;-   intermediate 101b (41 mg) as an oil.    Intermediate 101a:

T.I.c.: CH/AcOEt 7:3, Rf=0.43.

MS (ES/+): m/z=404 [M+Na]⁺.

Intermediate 101b:

T.I.c.: CH/AcOEt 7:3, Rf=0.36.

MS (ES/+): m/z=404 [M+Na]⁺.

Intermediate 102

3-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinyl)-3-(4-fluorophenyl)propanoicacid (diastereoisomer A)

A solution of lithium hydroxide monohydrate (21 mg) in water (0.5 mL)was added to a solution of intermediate 101a (38 mg) in MeOH (2 mL). Themixture was heated to 80° C. for 1 hour, then it was allowed to cool tor.t. The residue was acidified with 1M hydrochloric acid solution andextracted with DCM. The organic layer was dried and concentrated invacuo to give the title compound (37 mg) as a foam.

MS (ES/−): m/z=352 [M−H]⁻.

Intermediate 103

3-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinyl)-3-(4-fluorophenyl)propanoicacid (diastereoisomer B)

A solution of lithium hydroxide monohydrate (23 mg) in water (0.5 mL)was added to a solution of intermediate 101b (41 mg) in MeOH (2 mL). Themixture was heated to 80° C. for 1 hour, then it was allowed to cool tor.t. The residue was acidified with 1M hydrochloric acid solution andextracted with DCM. The organic layer was dried and concentrated invacuo to give the title compound (40 mg) as a foam.

MS (ES/−): m/z=352 [M−H]⁻.

Intermediate 104

1,1-dimethylethyl2-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-morpholinecarboxylate(104a) (diastereoisomer 1) and 1,1-dimethylethyl2-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-morpholinecarboxylate(104b) (diastereoisomer 2)

DIPEA (52 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (49 mg) were added to a solution of intermediate 102(37 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 1 hour,(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (32 mg) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith AcOEt and washed with water. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH, CH/AcOEt from 9:1 to 7:3) to give:

-   intermediate 104a (31 mg) as oil.-   intermediate 104b (20 mg) as oil.    Intermediate 104a:

T.I.c.: CH/AcOEt 1:1, Rf=0.73.

MS (ES/+): m/z=629 [M+Na]⁺, 607 [M+H]⁺.

Intermediate 104b:

T.I.c.: CH/AcOEt 1:1, Rf=0.65.

MS (ES/+): m/z=629 [M+Na)⁺, 607 [M+H]⁺.

Intermediate 105

1,1-dimethylethyl2-[3-[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-4-morpholinecarboxylate(105a) (diastereoisomer 3) and 1,1-dimethylethyl2-[3-[{(1R)-1-3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxoproyl]-4-morpholinecarboxylate(105b) (diastereoisomer 4)

DIPEA (62 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (57 mg) were added to a solution of intermediate 103(40 mg) in anhydrous DMF (3 mL) under a Nitrogen atmosphere. Afterstirring for 1 hour,(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (35 mg) wasadded. The mixture was stirred at r.t. overnight, then it was dilutedwith AcOEt and washed with water. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH, CH/AcOEt from 9:1 to 7:3) to give:

-   intermediate 105a (16 mg) as oil.-   intermediate 105b (19 mg) as oil.    Intermediate 105a:

T.I.c.: CH/AcOEt 1:1, Rf=0.56.

MS (ES/+): m/z=629 [M+Na]⁺, 607 [M+H]⁺.

Intermediate 105b:

T.I.c.: CH/AcOEt 1:1, Rf=0.46.

MS (ES/+): m/z=629 [M+Na]⁺, 607 [M+H]⁺.

Intermediate 106

1,1-dimethylethyl 3-[(1E)-3-(ethyloxy)-1-(4-fluorophenyl)-3-oxo-1-propen-1-yl]-1-piperidinecarboxylate

Triethylphosphono Acetate (0.3 mL) was dropped into a sospension of NaH(60% in mineral oil, 62 mg) in anhydrous THF (3 mL) previously cooled to0° C. under a Nitrogen atmosphere. At the end of the addition themixture was allowed to warm to r.t. and stirred for 20 minutes. Thenintermediate 68 (120 mg) dissolved in anhydrous THF (3 mL) was added andthe mixture was stirred at reflux temperature. After 3 hours the mixturewas allowed to reach r.t. and was treated with water and extracted withEt2O. The organic layer was dried and concentrated in vacuo to a residuewhich was purified by flash chromatography (CH/AcOEt (9:1) to give thetitle compound (100 mg) as a yellow oil.

T.I.c.: CH/AcOEt 8:2, Rf=0.5 and Rf=0.4 (detection with ninhydrine).

NMR (CD3OD): δ (ppm) 7.2-7.0 (m, 4H); 5.88 (s, 1H); 4.1 (b, 1H); 4.02(b, 1H); 3.99 (q, 2H); 2.68 (m 1H); 2.6 (m, 1H); 2.40 (m, 1H); 1.92 (m,1H); 1.4-1.6 (m, 2H); 1.58 (s, 9H), 1.09 (t, 3H).

MS (ES/+): m/z=378 [M+H]⁺.

Intermediate 107

1,1-dimethylethyl3-[3-(ethyloxy)-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate

Magnesium turnings (33 mg) were added to a solution of intermediate 106(100 mg) in anhydrous MeOH (2.65 mL) under a Nitrogen atmosphere with alow heating until hydrogen evolution is observed. Then, the reactionmixture was stirred at r.t. for 3 hours, then water (2 mL) and aceticacid 10% v/v was added (2 ml). Ammonium hydroxy saturated solution (3ml) was added until ph=8. The acqueous solution was extracted with Et2O.The organic phase was dried and concentrated in vacuo to give the titlecompounds (87 mg) as a colourless oil.

T.I.c.: CH/AcOEt 7:3, Rf 0.45 (detection with ninhydrine).

MS (ES/+): m/z=402 [M+Na]⁺.

Intermediate 108

3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-piperidinyl)-3-(4-fluorophenyl)propanoicacid

A solution of lithium hydroxide monohydrate (48 mg) in water (0.7 mL)was added to a solution of intermediate 107 (87 mg) in MeOH (2.7 mL).The mixture was heated to 65° C. for 2 hour, then it was allowed to coolto r.t., acidified with 1M hydrochloric acid solution and extracted withDCM. The organic layer was washed with water, dried and concentrated invacuo to give the title compound (75 mg) as a colourless oil.

T.I.c.: CH/AcOEt 1:1, Rf 0.18 (detection with ninhydrine).

MS (ES/−): m/z=350 [M−H]⁻.

Intermediate 109

1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(109a) (diasteroisomer A) and 1,1-dimethylethyl3-[3-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]-1-(4-fluorophenyl)-3-oxopropyl]-1-piperidinecarboxylate(109b) (diasteroisomer B)

TEA (0.090 mL) andO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.106 g) were added to a solution of intermediate108 (0.075 g) in anhydrous DCM (1 mL) under a Nitrogen atmosphere. Afterstirring for 20 minutes,{[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine hydrochloride (0.075g) was added. The mixture was stirred at r.t. overnight, then it wasdiluted with AcOEt and washed with water. The organic layer was dried,concentrated in vacuo to a residue that was purified by flashchromatography (CH/AcOEt 9:1) to give:

-   intermediate 109a (17.6 mg) as colourless oil;-   intermediate 109b (41.6 mg) as colourless oil.    Intermediate 109a

T.I.c.: CH/AcOEt 7:3, Rf=0.5.

NMR (CDCl3): δ (ppm) 7.74 (s, 1H); 7.49 (s, 2H); 7.12 (m, 2H); 6.93 (m,2H); 4.66-4.41 (dd, 2H); 3.80 (m, 1H); 3.10-2.5 (m, 4H); 2.97 (dd, 2H);2.87 (s, 3H); 2.60 (m, 1H); 1.8-1.4 (m, 4H); 1.45 (s, 9H).

MS (ES/+): m/z=491 [M+H-BOC]⁺.

Intermediate 109b

T.I.c.: CH/AcOEt 7:3, Rf=0.35.

NMR (CDCl3): δ (ppm) 7.76 (s, 1H); 7.51 (s, 2H); 7.4 (m, 2H); 6.94 (m,2H); 4.66-4.47 (dd, 2H); 4.00 (m, 1H); 3.10-2.0 (m, 4H); 2.97 (dd, 2H);2.84 (s, 3H); 2.6 (m, 1H); 1.8-1.4 (m, 4H); 1.42 (s, 9H).

MS (ES/+): m/z=491 [M+H-BOC]⁺.

Intermediate 110

Ethyl (2E)-2-cyano-3-(4-pyridinyl)-2-propenoate

A mixture of 4-pyridinecarbaldehyde (5.0 g), ethyl cyanoacetate (5.46mL), ammonium acetate (1.98 g) and acetic acid (2.67 mL) in anhydroustoluene (100 mL) was heated to 85° C. for 4 hours, then it was allowedto cool to r.t. and washed with water, 1N sodium hydroxide solution andbrine. The organic phase was dried and concentrated in vacuo to aresidue, which was purified by crystallisation from MeOH to give thetitle compound (3.29 g) as a white solid.

T.I.c.: AcOEt, Rf=0.39.

NMR (CDCl3): δ (ppm) 8.85 (d, 2H); 8.23 (s, 1H); 7.78 (d, 2H); 4.45 (q,2H); 1.45 (t, 3H).

MS (ES/+): m/z=203 [M+H]⁺.

Intermediate 111

Ethyl 2-cyano-3-(4-fluorophenyl)-3-(4-pyridinyl)propanoate

A solution of 4-fluorophenyl magnesium bromide (1M in THF—14.83 mL) inanhydrous Et2O (17 mL) was dropped into a solution of intermediate 110(1.0 g) in anhydrous Et2O (17 mL) previously heated to reflux under aNitrogen atmosphere. The mixture was heated at reflux for 30 minutes,then cooled to 0° C. and treated with 3M sulfuric acid solution (4 mL)diluted with AcOEt and the layers were separated. The aqueous layer wasextracted with further AcOEt. The combined organic extracts were washedwith a saturated sodium hydrogen carbonate solution then dried andconcentrated in vacuo. The residue was purified by flash chromatography(CH, then CH/AcOEt from 90:10 to 85:15) to give the title compound (1.1g) as a white foam.

T.I.c.: AcOEt, Rf=0.39.

MS (ES/+): m/z=299 [M+H]⁺.

Intermediate 112

3-(4-Fluorophenyl)-3-(4-pyridinyl)propanoic acid

A mixture of intermediate 111 (265 mg) in acetic acid (4.5 mL), concsulfuric acid (1.5 mL) and water (1.5 mL) was heated to 140° C. for 3hours. The solution was allowed to cool to 0° C. and saturated sodiumhydrogen carbonate solution followed by a 2.5M sodium hydroxide solutionwere added. AcOEt was added, and the aqueous phase extracted three timeswith AcOEt. The combined organic extracts were dried and concentrated invacuo. The residue was triturated with AcOEt to give the title compound(105 mg) as a white solid.

IR (nujol, cm⁻¹): 1701 (str. C═O).

MS (ES/+): m/z=246 [M+H]⁺.

EXAMPLE 1N-(3,5-Bis-trifluoromethyl-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide

TFA (0.8 mL) was added to a solution of intermediate 7 (0.06 g) in DCM(1 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 3 hours, then the solution was diluted with further DCM andwashed with a saturated potassium carbonate solution and brine. Thecombined organic extracts were dried, concentrated in vacuo and theresidue was purified by flash chromatography (from AcOEt to AcOEt/MeOH1:1 and finally to AcOEt/MeOH 4:6 containing 2% of conc. ammoniumhydroxide solution) to give the title compound (0.043 g) as a paleyellow oil.

T.I.c.: AcOEt/MeOH 1:1 containing 2% of conc. NH4OH, Rf=0.1.

IR (film, cm⁻¹): 3320 (NH), 1646 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.95 (s, 1H); 7.7 (s, 2H); 7.17 (s, 2H); 6.98(dd, 2H); 4.54 (q, 2H); 2.94 (s, 3H); 2.92-2.71 (m, 5H); 2.4-2.24 (2td,2H); 1.69-1.43 (m, 2H); 1.2 (db, 1H); 1.04-0.75 (2qd, 2H).

MS (ES/+): m/z=491 [M+H]⁺.

EXAMPLE 2N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide

TFA (0.73 mL) was added to a solution of intermediate 8 (0.048 g) in DCM(0.96 mL) under a Nitrogen atmosphere. The resulting solution wasstirred at r.t. for 3 hours, then the solution was diluted with furtherDCM and washed with a saturated potassium carbonate solution and brine.The combined organic extracts were dried, concentrated in vacuo and theresidue was purified by flash chromatography (from AcOEt to AcOEt/MeOH1:1 and finally to AcOEt/MeOH 4:6 containing 2% of conc. ammoniumhydroxide solution) to give the title compound (0.031 g) as a paleyellow oil.

T.I.c.: AcOEt/MeOH 1:1 containing 2% of conc. NH4OH, Rf=0.08.

IR (film, cm⁻¹): 3320 (NH), 1646 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.43 (t, 1H); 7.2 (dd, 2H); 7.04 (dd, 2H); 6.98(s, 2H); 4.37 (q, 2H); 2.89 (s, 3H); 2.94-2.7 (m, 5H); 2.4-2.19 (2td,2H); 1.74-1.15 (m, 3H); 1.04-0.77 (m, 2H).

MS (ES/+): m/z=423 [M+H]⁺.

EXAMPLE 3N-(3,5Dichloro-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(3a) (enantiomer 1) andN-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(3b) (enantiomer 2)

The compound of example 2 (10 mg) was separated into the enantiomers viaHPLC (Column: Chiralcel OD 25 cm×4.6 mm; mobile phase: n-hexane/EtOH70:30; flux=1 mL/min; λ=225 nm). Thus, example 3a (3 mg) and example 3b(1.8 mg) were obtained.

EXAMPLE 3a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 70:30, flux=1 mL/min, λ=225 nm, retention time 5.8minutes. Ratio 3a/3b=100:0.

EXAMPLE 3b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 70:30, flux=1 mL/min, λ=225 nm, retention time 10.2minutes. Ratio 3a/3b=0:100.

EXAMPLE 4N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide

TFA (1.5 mL) was added to a solution of intermediate 13a (0.17 g) in DCM(6 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 30 minutes, then the solution was diluted with further DCMand washed with a saturated potassium carbonate solution. The organicextracts were dried and concentrated in vacuo to give the crude titlecompound (136 mg). A part of the residue (64 mg) was purified on SCXcartridge (ammonium hydroxide 0.25 M in MeOH) to give the title compound(60 mg) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.06 (t, 2H); 7.18 (m, 2H); 7.15 (s, 2H); 7.48(s, 1H); 5.58 (q, 1H); 2.91-2.8 (2m, 2H); 2.91-2.4 (2 m, 2H); 2.8-2.25(t+m, 2H); 2.64 (s, 3H); 2.6 (m, 1H); 1.67-0.99 (q+d, 2H); 1.2 (s, 3H);1.2-0.83 (2m, 2H).

MS (ES/+): m/z=437 [M+H]⁺.

EXAMPLE 5N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide

TFA (1.5 mL) was added to a solution of intermediate 13b (0.17 g) in DCM(6 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 30 minutes, then the solution was diluted with further DCMand washed with a saturated potassium carbonate solution. The organicextracts were dried and concentrated in vacuo to give the crude titlecompound (136 mg). A part of the residue (64 mg) was purified on SCXcartridge (ammonium hydroxide 0.25 M in MeOH) to give the title compound(60 mg) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.42 (s, 1H); 7.03 (t, 2H); 7.2 (dd, 2H); 6.85(s, 2H); 5.6 (q, 1H); 3.0-2.8 (m, 4H); 2.61 (s, 3H); 2.6 (m, 1H); 1.71(bd, 1H); 1.51-1.0 (2m, 2H); 1.32 (d, 3H); 1.16-0.84-(2m, 2H).

MS (ES/+): m/z=437 [M+H]⁺.

EXAMPLE 6N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(6a) (diastereoisomer 1) andN-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(6b) (diastereoisomer 2)

The compound of example 4 (35 mg) was separated into the enantiomers viaHPLC (Column: Chiralpack AD 25 cm×4.6 mm; mobile phase: n-hexane/EtOH80:20; flux=7 mL/min; 225 nm). Thus, example 6a (16 mg) and example 6b(14 mg) were obtained.

EXAMPLE 6a

Chiral HPLC: Column Chiralpack AD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ=225 nm, retention time 8.9minutes. Ratio 6a/6b=100:0.

EXAMPLE 6b

Chiral HPLC: Column Chiralpack AD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ=225 nm, retention time 10.7minutes. Ratio 6a/6b=0:100.

EXAMPLE 7N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(7a) (diastereoisomer 3) andN-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide(7b) (diastereoisomer 4)

The compound of example 5 (25 mg) was separated into the enantiomers viaHPLC (Column: Chiralcel OD 25 cm×4.6 mm; mobile phase: n-hexane/EtOH8:2; flux=1 mL/min; λ=225 nm). Thus, example 7a (9 mg) and example 7b (9mg) were obtained.

EXAMPLE 7a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 8:2, flux=1 mL/min, λ=225 nm, retention time 6.7 minutes.Ratio 7a/7b=100:0.

EXAMPLE 7b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm, mobile phasen-hexane/EtOH 8:2, flux=1 mL/min, λ225 nm, retention time 10.1 minutes.Ratio 7a/7b=0:100.

EXAMPLE 8N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-[1-(2-methoxyethyl)-piperidin-4-yl]-propionamide(diastereoisomer A)

A mixture of example 4 (72 mg), DIPEA (115 μL) and 2-bromoethyl methylether (19 μL) in acetonitrile (5 mL) was heated to reflux overnight.Water was added and the mixture was concentrated in vacuo. The residuewas dissolved in AcOEt and washed with a saturated ammonium chloridesolution. The layers were separated. The organic layer was extractedwith further AcOEt. The combined organic extracts were dried andconcentrated in vacuo to a residue which was purified by flashchromatography (DCM/MeOH 9:1) to give the title compound (57 mg) as acolourless oil.

NMR (d₆-DMSO): δ (ppm) 7.48 (s, 1H); 7.2 (m, 2H); 7.15 (s, 2H); 7.06 (t,2H); 5.58 (q, 1H); 3.35 (t, 2H); 3.18 (s, 3H); 2.94-2.86 (2m, 2H);2.9-2.4 (2 m, 2H); 2.8-2.25 (t+m, 2H); 2.63 (s, 3H); 2.6 (m, 1H); 2.37(dd, 2H); 1.85-1.12 (q+t, 2H); 1.73-0.97 (2q, 2H); 1.2 (s, 3H);.

MS (ES/+): m/z=495 [M+H]⁺.

EXAMPLE 9N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-[1-(2-methoxyethyl)-piperidin-4-yl]-propionamide(diastereoisomer B)

A mixture of example 5 (79 mg), DIPEA (126 μL) and 2-bromoethyl methylether (20 μL) in acetonitrile (5 mL) was heated to reflux overnight.Water was added and the mixture was concentrated in vacuo. The residuewas dissolved in AcOEt and washed with a saturated ammonium chloridesolution. The layers were separated. The organic layer was extractedwith further AcOEt. The combined organic extracts were dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (DCM/MeOH 95:5) to give the title compound (35 mg) as acolourless oil.

NMR (d₆-DMSO): δ (ppm) 7.42 (s, 1H); 7.15 (s, 2H); 7.04 (t, 2H); 6.85(s, 2H); 5.6 (q, 1H); 3.37 (t, 2H); 3.19 (s, 3H); 3.0-2.8 (m, 6H); 2.61(s, 3H); 2.41 (bs, 2H); 1.76 (d, 1H); 1.45-1.21 (2m, 2H); 1.32 (d, 3H);1.27-0.99 (q, 2H); 1.21 (m, 1H).

MS (ES/+): m/z=495 [M+H]⁺.

EXAMPLE 10N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamide

A solution of TFA (1 mL) in anhydrous DCM (3 mL) was added to a solutionof intermediate 23 (64 mg) in anhydrous DCM (1 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The resulting solution was stirredat −10° C. for 2 hours, then the solution was concentrated in vacuo. Theresidue was diluted with AcOEt/water and washed with a saturatedpotassium carbonate solution. The aqueous layer was extracted withfurther AcOEt (3×20 mL). The combined organic extracts were dried andconcentrated in vacuo to a residue which was purified by flashchromatography (DCM/MeOH 8:2) to give the title compound (40 mg) as awhite foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.1.

NMR (d₆-DMSO): δ (ppm) 7.42 (t, 1H); 7.28 (dd, 2H); 7.07 (dd, 2H); 6.95(d, 2H); 4.51 (d, 1H); 4.23 (d, 1H); 3.38 (m, 1H); 2.97 (dd, 1H); 2.94(s, 3H); 2.86 (dd, 1H); 2.74 (m, 1H); 2.66 (m, 1H); 2.63 (m, 1H); 2.54(m, 1H); 1.78 (m, 1H); 1.47 (m, 1H); 1.4 (m, 1H); 1.34 (m, 1H).

EXAMPLE 11N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamidehydrochloride

Hydrochloric acid (1 m in Et2O—20 μL) was added to a solution of example10 (7.8 mg) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (5 mg) as a white solid.

MS (ES/+): m/z=441 [M+H-HCl]⁺.

EXAMPLE 12N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamide(12a—enantiomer 1) andN-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamide(12b—enantiomer 2)

The compound of example 10 (32 mg) was separated into the enantiomersvia HPLC (Column: Chiralcel OD 25 cm×20 mm; mobile phase: n-hexane/EtOH70:30; flux=6.4 mL/min; 225 nm). Thus, example 12a (15 mg) and example12b (14 mg) were obtained.

EXAMPLE 12a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5μ, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ225 nm, retention time 8.1 minutes.Ratio 12a/12b=100:0.

EXAMPLE 12b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×51, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ=225 nm, retention time 22.4minutes. Ratio 12a/12b=0:100.

EXAMPLE 13N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamidehydrochloride

Hydrochloric acid (1M in Et2O—38 μL) was added to a solution of example12a (15 mg) in anhydrous Et2O (1.5 mL) previously cooled to −10° C.under a Nitrogen atmosphere. The mixture was stirred at −10° C. for 30minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (2×1 mL) and pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (11 mg) as white solid.

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5μ, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ=225 nm, retention time 7.96minutes.

MS (ES/+): m/z=441 [M+H-HCl]⁺.

EXAMPLE 14N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamidehydrochloride

Hydrochloric acid (1M in Et2O—35 μL) was added to a solution of example12b (14 mg) in anhydrous Et2O (1.5 mL) previously cooled to −10° C.under a Nitrogen atmosphere. The mixture was stirred at −10° C. for 30minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (2×1 mL) and pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (10 mg) as a white solid.

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5μ, mobile phasen-hexane/EtOH 80:20, flux=1 mL/min, λ=225 nm, retention time 22.2minutes.

NMR (d₆-DMSO): δ (ppm) 8.39 (bm, 1H); 7.39 (s, 1H); 7.31 (dd, 2H); 7.08(dd, 2H); 6.92 (s, 2H); 4.5 (d, 1H); 4.18 (d, 1H); 3.47 (m, 1H); 3.17(m, 1H); 3.12 (m, 1H); 3.02 (dd, 1H); 2.92 (s, 3H); 2.89 (m, 1H); 2.85(dd, 1H); 2.82 (m, 1H); 2.06 (m, 1H); 1.75 (m, 1H); 1.65 (m, 2H);

MS (ES/+): m/z=441 [M+H-HCl]⁺.

EXAMPLE 15N-(3,5-Bis-trifluoromethyl-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamidehydrochloride

Hydrochloric acid (1M in Et2O—12 μL) was added to a solution of example1 (5 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then it was concentrated in vacuo. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (5 mg) as a white solid.

MS (ES/+): m/z=491 [M+H]⁺.

EXAMPLE 16N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4fluorophenyl)-N-methyl-3-{1-[2-(methyloxy)ethyl]-4-piperidinyl}propionamide

A mixture of example 1 (10 mg), DIPEA (14 μL) and 2-bromoethyl methylether (2.1 μL) in acetonitrile (0.5 mL) was heated to reflux overnight.Water was added and the mixture was concentrated in vacuo. The residuewas dissolved in DCM and washed with water. The layers were separated.The aqueous layer was extracted with further DCM (2×5 ml). The combinedorganic extracts were dried and concentrated in vacuo to a residue,which was purified by flash chromatography (from AcOEt to AcOEt/MeOH4:6) to give the title compound (6 mg) as a colourless oil.

T.I.c.: AcOEt/MeOH 1:1, Rf=0.18.

MS (ES/+): m/z=549 [M+H]⁺.

EXAMPLE 17N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-{1-[2-(methyloxy)ethyl]-4-piperidinyl}propionamidehydrochloride

Hydrochloric acid (1M in Et2O—13.2 μL) was added to a solution ofexample 16 (6 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C.under a Nitrogen atmosphere. The mixture was stirred at 0° C. for 15minutes, then the liquid phase was removed. The residue was trituratedwith pentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give thetitle compound (5 mg) as a white solid.

MS (ES/+): m/z=549 [M+H]⁺.

EXAMPLE 18N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamidehydrochloride (diastereoisomer 1)

TFA (1 mL) was added to a solution of intermediate 24a (28 mg) in DCM (5mL) under a Nitrogen atmosphere. The resulting solution was kept at −18°C. overnight, then the solution was diluted with further DCM and washedwith a saturated potassium carbonate solution. The combined organicextracts were dried, concentrated in vacuo. The residue was purified byflash chromatography (AcOEt/MeOH 1:1 and finally to AcOEt/MeOH 1:1containing 1% of TEA) to give a compound (15 mg) that was dissolved inEt2O (0.7 mL). To this solution cooled to 0° C. under a Nitrogenatmosphere hydrochloric acid (1M in Et2O—32 μL). The mixture was stirredat 0° C. for 30 minutes, then it was concentrated in vacuo. The residuewas triturated with pentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL)to give the title compound (13 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 7.97 (s, 1H); 7.74 (s, 2H); 7.19 (dd, 2H); 7.06(dd, 2H); 5.66 (q, 1H); 3.20 (bd, 1H); 3.12 (bd, 1H); 2.97 (m, 1H); 2.79(dd, 1H); 2.76 (dd, 1H); 2.69 (m, 1H); 2.67 (s, 3H); 2.64 (m, 1H); 1.87(bd, 1H); 1.74 (m, 1H); 1.40 (bd, 1H); 1.29 (d, 3H); 1.22 (m, 1H); 1.09(bq, 1H).

EXAMPLE 19N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamidehydrochloride(diastereoisomer 2)

TFA (1 mL) was added to a solution of intermediate 24b (31 mg) in DCM (5mL) under a Nitrogen atmosphere. The resulting solution was kept at −18°C. overnight, then the solution was diluted with further DCM and washedwith a saturated potassium carbonate solution. The combined organicextracts were dried, concentrated in vacuo. The residue was purified byflash chromatography (AcOEt/MeOH 1:1 and finally to AcOEt/MeOH 1:1containing 1% of TEA) to give a compound (free base, 11 mg) that wasdissolved in Et2O (0.7 mL). To this solution cooled to 0° C. under aNitrogen atmosphere hydrochloric acid (1M in Et2O—21 μL). The mixturewas stirred at 0° C. for 30 minutes, then it was concentrated in vacuo.The residue was triturated with pentane (2×1 mL) to give the titlecompound (11 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.54 (s, 2H); 7.18 (dd, 2H); 6.98(dd, 2H); 5.71 (q, 1H); 3.23 (bd, 1H); 3.13 (bd, 1H); 2.98 (m, 1H); 2.85(dd, 1H); 2.76 (dd, 1H); 2.66 (s, 3H); 2.66 (m, 1H); 2.65 (m, 1H); 1.88(bd, 1H); 1.74 (m, 1H); 1.41 (d, 3H); 1.39 (bd, 1H); 1.25 (m, 1H); 1.09(bq, 1H).

EXAMPLE 20N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide(diastereoisomer 1)

TFA (1.5 ml) was added to a solution of intermediate 25a (198 mg) in DCM(6 ml) under a Nitrogene atmosphere. The resulting solution was stirredat r.t. for 30 min, then it was diluted with DCM and washed with asaturated potassium carbonate solution and brine. The organic layer wasdried, concentrated in vacuo and the residue was purified by SCXcartridge (load with DCM and elution with MeOH, NH₃ 0.25M in MeOH) togive the title compound as a colourless foam.

NMR (d₆-DMSO): δ (ppm) 7.95 (s, 1H); 7.73-7.56 (s, 2H); 7.16-6.86 (m,2H); 5.68-5.44 (m, 1H); 2.65 (s, 3H); 3.0-2.2 (m, 4H); 3.0-2.2 (m, 2H);3.0-2.5 (m, 1H); 1.7-0.7 (m, 5H); 1.26 (d, 3H).

MS (ES/+): m/z=505 [M+H]⁺.

EXAMPLE 21N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide(diastereoisomer 2)

TFA (1.5 ml) was added to a solution of intermediate 25b (165 mg) in DCM(6 ml) under a Nitrogene atmosphere. The resulting solution was stirredat r.t. for 30 min, then it was diluted with DCM and washed with asaturated potassium carbonate solution and brine. The organic layer wasdried, concentrated in vacuo and the residue was purified by by SCXcartridge (load with DCM and elution with MeOH, NH₃ 0.25M in MeOH) togive the title compound as a colourless foam.

NMR (d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.56 (s, 2H); 7.17 (m, 2H); 6.96(t, 2H); 5.74 (q, 1H); 3.00-2.7 (m, 4H); 2.8-2.7 (m, 1H); 2.4-2.2 (m,2H); 1.7-1.0 (m, 2H); 1.5 (m, 1H); 1.2-0.8 (m, 2H); 2.67 (s, 3H); 1.43(d, 3H).

MS (ES/+): m/z=505 [M+H]⁺.

EXAMPLE 22N-{1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-3-(4-fluorophenyl)-3-(4-piperidinyl)propionamide

TFA (0.5 mL) was added to a solution of intermediate 26 (29 mg) inanhydrous DCM (1 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wasevaporated at 0° C. and treated with a 10% sodium hydrogen carbonatesolution until pH=10. The aqueous layer was extracted with DCM (3×8 mL).The combined organic extracts were dried, concentrated in vacuo and theresidue was purified by flash chromatography (DCM/MeOH from 98:2 to75:25) to give the title compound as a white solid (17 mg).

T.I.c.: DCM/MeOH 8:2, Rf=0.03 (detection with ninhydrine).

NMR (CDCl3): δ (ppm) 7.69 (s, 1H); 7.60 (s, 2H); 7.12 (dd, 2H); 7.01 (t,2H); 5.45 (s, 1H); 3.11 (d, 1H); 2.99 (d, 1H); 2.84 (m, 1H); 2.69 (dd,1H); 2.57 (dt, 1H); 2.46 (dt, 1H); 2.33 (dd, 1H); 1.79 (d, 1H); 1.60 (m,1H); 1.46 (s, 3H); 1.43 (s, 3H); 1.33 (d, 1H); 1.16 (dt, 1H); 1,00 (dt,1H).

MS (ES/+): m/z=505 [M+H]⁺.

EXAMPLE 23N-{1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

TFA (0.5 mL) was added to a solution of intermediate 27 (50 mg) inanhydrous DCM (1 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wasevaporated at 0° C. and treated with a 10% sodium hydrogen carbonatesolution until pH=10. The aqueous layer was extracted with DCM (3×8 mL).The combined organic extracts were dried, concentrated in vacuo and theresidue was purified by flash chromatography (DCM/MeOH from 100:0 to75:25) to give the title compound as a white solid (23 mg).

T.I.c.: DCM/MeOH 8:2, Rf=0.05 (detection with ninhydrine).

NMR (CDCl3): δ (ppm) 7.64 (s, 1H); 7.54 (s, 2H); 7.06 (dd, 2H); 6.96 (t,2H); 3.19 (d, 1H); 3.09 (d, 1H); 3.03 (s, 3H); 2.95 (m, 1H); 2.71 (dd,1H); 2.64 (m, 1H); 2.61 (dt, 1H); 2.52 (dt, 1H); 1.90 (m, 1H); 1.62 (m,1H); 1.53 (s, 3H); 1.50 (s, 3H); 1.39 (d, 1H); 1.27 (m, 1H); 1.12 (m,1H).

MS (ES/+): m/z=519 [M+H]⁺.

EXAMPLE 24N-{[3-bromo-4-(methyloxy)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

Intermediate 28 were dissolved in dry DCM (3.6 ml) and trifluoroaceticacid (400 μl) was added. The mixtures were stirred at r.t. for 3 hours,then they were concentrated in vacuo. The residue was purified bysemipreparative HPLC (column: X Terra MS C18 100×30 mm, 5 μm; mobilephase: A: H₂O+0.1% TFA; B: CH₃CN+0.1% TFA; gradient: 30% (B) for 1 min,from 30% (B) to 90% (B) in 12 min., 90% (B) for 2 min; flow rate=43mL/min; detection: λ=200-400 nm); the solution recovered wasconcentrated in vacuo, and the residue was dissolved in 5% sodiumhydrogen carbonate solution (5 mL) and extracted with DCM (2×8 mL),which was passed through a phase separation cartridge with polypropylenefrit and concentrated in vacuo. to obtain the title compound_(14 mg) asa yellow foam.

NMR (CDCl3): δ (ppm) 7.27-6.72 (m, 7H); 4.55 (dd, 1H); 4.19 (dd, 1H);3.87 (s, 3H); 3.19-3.04 (m, 1H); 3.19-3.04 (m, 2H); 2.79 (s, 3H);2.82-2.7 (m, 2H); 2.82-2.49 (m, 2H); 1.7 (m, 1H); 1.7/1.4-1.0 (m, 2H);1.4-1.0 (m, 2H).

MS (ES/+): m/z=463 [M+H]⁺.

Following the general procedure described for the preparation of example24 the Examples 25-28 were obtained:

EXAMPLE 25N-{[3,5-dimethylphenyl)methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

Starting from intermediate 29 the title compound (20 mg) was obtained asa yellow foam.

NMR (CDCl3): δ (ppm) 7.15 (dd, 2H); 6.97 (t, 2H); 6.86 (d, 1H); 6.62 (s,2H); 4.52 (d, 1H); 4.28 (d, 1H); 3.18 (m, 1H); 3.13 (m, 1H); 3.05 (m,1H); 2.80 (s, 3H); 2.76 (dd, 1H); 2.66 (dd, 1H); 2.63 (m, 1H); 2.52 (m,1H); 2.28 (s, 3H); 2.24 (s, 3H); 1.87 (bd, 1H); 1.67 (m, 1H); 1.40 (m,1H); 1.28 (m, 1H); 1.08 (m, 1H)

MS (ES/+): m/z=383 [M+H]⁺.

EXAMPLE 26N-[(3,4-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

Starting from intermediate 30 the title compound (15 mg) was obtained asa yellow foam.

NMR (CDCl3): δ (ppm) 7.44 (d 1H); 7.29 (d, 1H); 7.14 (dd, 2H); 6.93 (dd,2H); 6.63 (dd, 1H); 4.55 (d, 1H); 4.21 (d, 1H); 3.13 (bd, 1H); 3.08 (m,1H); 3.00 (bd, 1H); 2.82 (s, 3H); 2.76 (dd, 1H); 2.70 (dd, 1H); 2.59 (m,1H); 2.48 (m, 1H); 1.83 (bd, 1H); 1.62 (m, 1H); 1.36 (bd, 1H); 1.21 (m,1H); 1.02 (m, 1H);

EXAMPLE 27N-[(3-fluoro-2-methylphenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

Starting from intermediate 31 the title compound (26 mg) was obtained asa yellow foam.

NMR (CDCl₃): δ (ppm) 7.17 (m, 2H); 7.10-6.85 (m, 4H); 6.35 (d, 1H); 4.71(d, 1H); 4.28 (d, 1H); 4.32 (dd, 2H); 3.2-2.95 (m, 4H); 2.75-2.4 (m,3H); 2.86 (s, 3H); 2.02 (s, 3H); 1.9-1.6 (m, 3H); 1.4-0.95 (m, 2H).

EXAMPLE 28N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide

Starting from intermediate 32 the title compound (8 mg) was obtained asa yellow foam.

NMR (CDCl3): δ (ppm) 7.56 (d, 2H); 7.20-7.10 (m, 2H); 7.05-7.00 (m, 2H);6.93 (t, 1H); 6.54 (d, 1H); 4.88 (d, 1H); 4.50 (dd, 2H); 4.39 (d, 1H);3.2-2.95 (m, 4H); 2.80-2.40 (m, 3H); 2.92 (s, 3H); 1.90-1.60 (m, 3H);1.4-0.95 (m, 2H).

EXAMPLE 29N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methyltropionamide(diastereoisomer 1)

TFA (1.0 mL) was added to a solution of intermediate 33a (50 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluted with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 7/3) to give the title compound (0.033 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

MS (ES/+): m/z=523 [M+H]⁺.

EXAMPLE 30N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer 1)

Hydrochloric acid (1M in Et2O—70 μL) was added to a solution of example29 (33 mg) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (33 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 8.75 (bm, 1H); 8.4 (bm, 1H); 8.0 (s, 1H); 7.8 (s,2H); 7.25 (m, 2H); 7.1 (m, 2H); 5.65 (q, 1H); 3.55 (m, 1H); 3.2 (bm,2H); 3.05-2.75 (m, 4H); 2.74 (s, 3H); 2.05 (bm, 1H); 1.75 (bm, 3H); 1.35(d, 3H).

MS (ES/+): m/z=523 [M+H-HCl]⁺.

EXAMPLE 31N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(diastereoisomer 2)

TFA (1.0 mL) was added to a solution of intermediate 33b (55 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluted with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 7/3) to give the title compound (0.036 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

MS (ES/+): m/z=523 [M+H]⁺.

EXAMPLE 32N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer 2)

Hydrochloric acid (1M in Et2O—76 μL) was added to a solution of example31 (36 mg) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (34 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 8.6 (bs, 2H); 7.95 (s, 1H); 7.55 (s, 2H); 7.35(t, 2H); 7.05 (t, 2H); 5.7 (q, 1H); 3.5 (m, 1H); 3.25-2.8 (m, 6H); 2.75(s, 3H); 2.05 (bm, 1H); 1.8 (bm, 3H); 1.45 (d, 3H).

MS (ES/+): m/z=523 [M+H-HCl]⁺.

EXAMPLE 33N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(diastereoisomer 1)

TFA (1.0 mL) was added to a solution of intermediate intermediate 34a(52 mg) in anhydrous DCM (4 mL) previously cooled at 0° C., under aNitrogen atmosphere. The solution was stirred at 0° C. for 2 hours, thenit was concentrated in vacuo at 0° C. The residue was taken up with asaturated solution of potassium carbonate (10 mL) and diluted with EtOAc(50 mL). The organic phase was separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The collected organic phases were dried,concentrated in vacuo and the residue was purified by flashchromatography (DCM/MeOH from 9/1 to 7/3) to give the title compound(0.042 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

MS (ES/+): m/z=523 [M+H]⁺.

EXAMPLE 34N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer 1)

Hydrochloric acid (1M in Et2O—90 μL) was added to a solution of example33 (42 mg) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (42 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 8.75 (bm, 1H); 8.4 (bm, 1H); 8.0 (s, 1H); 7.8 (s,2H); 7.25 (m, 2H); 7.1 (m, 2H); 5.65 (q, 1H); 3.55 (m, 1H); 3.2 (bm,2H); 3.05-2.75 (m, 4H); 2.74 (s, 3H); 2.05 (bm, 1H); 1.75 (bm, 3H); 1.35(d, 3H).

MS (ES/+): m/z=523 [M+H-HCl]⁺.

EXAMPLE 35N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(diastereoisomer 2)

TFA (1.0 mL) was added to a solution of intermediate 34b (50 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluted with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 7/3) to give the title compound (0.036 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

MS (ES/+): m/z=523 [M+H]⁺.

EXAMPLE 36N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer 2)

Hydrochloric acid (1M in Et2O—80 μL) was added to a solution of example35 (36 mg) in anhydrous Et2O (1 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) and with pentane/Et2O 1:1 (1.5 mL) to give the titlecompound (33 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 8.6 (bs, 2H); 7.95 (s, 1H); 7.55 (s, 2H); 7.35(t, 2H); 7.05 (t, 2H); 5.7 (q, 1H); 3.5 (m, 1H); 3.25-2.8 (m, 6H); 2.75(s, 3H); 2.05 (bm, 1H); 1.8 (bm, 3H); 1.45 (d, 3H).

MS (ES/+): m/z=523 [M+H-HCl]⁺.

EXAMPLE 37N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(37a) (enantiomer 1) andN-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(37b) (enantiomer 2)

TFA (15 mL) was added to a solution of intermediate 38 (765 mg) inanhydrous DCM (40 mL) previously cooled to −10° C. under a Nitrogenatmosphere. The solution was left in freezer overnight, then it wasconcentrated in vacuo. The residue was dissolved in DCM and washed withsaturated potassium carbonate solution. The aqueous layer was extractedwith further DCM. The organic extract was washed with brine, dried andconcentrated in vacuo to give the title compound (565 mg) as racemate.The mixture was separated into the enantiomers via HPLC (Column:Chiralcel OD 25 cm×2 cm; mobile phase: n-hexane/2-Propanol 70:30; flux=7mL/min; λ=225 nm).

Thus, example 37a (263 mg) and example 37b (264 mg) were obtained.

EXAMPLE 37a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm; mobile phase:n-hexane/2-Propanol 80:20; flux=1 mL/min; λ=225 nm, retention time 18.4minutes. ratio 37a/37b=100/0

MS (ES/+): m/z=439 [M+H]⁺.

EXAMPLE 37b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm; mobile phase:n-hexane/2-Propanol 80:20; flux=1 mL/min; λ=225 nm, retention time 35minutes. ratio 37a/37b=0/100

MS (ES/+): m/z=439 [M+H]⁺.

EXAMPLE 38N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride

Hydrochloric acid (1M in Et2O—0.6 mL) was added to a solution of example37a (261 mg) in anhydrous Et2O (5 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 10minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (3×5 mL) to give the title compound (264 mg) as whitesolid.

NMR (d₆-DMSO): δ (ppm) 8.54 (sb, 2H); 7.66 (s, 1H); 7.35 (dd, 2H); 7.18(s, 2H); 7.13 (t, 2H); 4.49-4.25 (dd, 2H); 3.55-3.46 (2dd, 1H);3.24-2.84 (m, 6H); 2.68 (s, 3H); 2.09 (m, 1H); 1.84-1.65 (m, 3H).

EXAMPLE 39N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride

Hydrochloric acid (1M in Et2O—0.6 mL) was added to a solution of example37b (261 mg) in anhydrous Et2O (5 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 10minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (3×5 mL) to give the title compound (265 mg) as whitesolid.

NMR (d₆-DMSO): δ (ppm) 8.54 (sb, 2H); 7.66 (s, 1H); 7.35 (dd, 2H); 7.18(s, 2H); 7.13 (t, 2H); 4.49-4.25 (dd, 2H); 3.55-3.46 (2dd, 1H); );3.24-2.84 (m, 6H); 2.68 (s, 3H); 2.09 (m, 1H); 1.84-1.65 (m, 3H).

EXAMPLE 40N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide-(diastereoisomer1)

TFA (1 mL) was added to a solution of intermediate 45a (51 mg) inanhydrous DCM (3 mL) previously cooled to −10° C. under a Nitrogenatmosphere. The solution was stirred for 1.5 hours, then it wasconcentrated in vacuo. The residue was dissolved in AcOEt/H₂O (10 mL/2ml) and washed with saturated potassium carbonate solution. The organiclayer was dried, concentrated in vacuo and the residue was purified bysilica cartridge (from DCM to DCM/MeOH 80:20) to give the title compound(32 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.40 (detection with ninhydrine).

MS (ES/+): m/z—573 [M+H]⁺.

EXAMPLE 41N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride-(diastereoisomer 1)

Hydrochloric acid (1M in Et2O—80 μL) was added to a solution of example40 (32 mg) in anhydrous Et2O (2 mL) previously cooled to −10° C. under aNitrogen atmosphere. The mixture was stirred at −10° C. for 10 minutes,then it was concentrated in vacuo. The residue was triturated withpentane (3×2 mL) to give the title compound (27 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 8.50 (sb, 2H); 8.00 (s, 1H); 7.80 (s, 2H); 7.58(s, 1H); 7.45 (dd, 2H); 5.65 (q, 1H); 4.03 (m, 1H); 3.23-2.87 (m, 6H);2.82 (s, 3H); 2.17 (m, 1H); 1.60 (m, 1H); 1.94-1.78 (m, 2H); 1.37 (d,3H).

MS (ES/+): m/z=573 [MH-HCl]⁺.

EXAMPLE 42N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide-(diastereoisomer2)

(TFA (1 mL) was added to a solution of intermediate 45b (57 mg) inanhydrous DCM (3 mL) previously cooled to −10° C. under a Nitrogenatmosphere. The solution was stirred for 1.5 hours, then it wasconcentrated in vacuo. The residue was dissolved in AcOEt/H₂O (10 mL/2ml) and washed with saturated potassium carbonate solution. The organiclayer was dried, concentrated in vacuo and the residue was purified bysilica cartridge (from DCM to DCM/MeOH 80:20) to give the title compound(28 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.39 (detection with ninhydrine).

MS (ES/+): m/z=573 [M+H]⁺.

EXAMPLE 43N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride-(diastereoisomer 2)

Hydrochloric acid (1M in Et2O—80 μL) was added to a solution of example42 (32 mg) in anhydrous Et2O (2 mL) previously cooled to −10° C. under aNitrogen atmosphere. The mixture was stirred at −10° C. for 10 minutes,then it was concentrated in vacuo. The residue was triturated withpentane (3×2 mL) to give the title compound (27 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 8.44 (sb, 2H); 7.95 (s, 1H); 7.57 (s, 2H); 7.57(s, 1H); 7.51 (d, 1H); 7.31 (d, 1H); 5.73 (q, 1H); 4.02 (m, 1H);3.23-2.82 (m, 6H); 2.78 (s, 3H); 2.18/1.60 (m, 2H); 1.92-1.78 (m, 2H);1.47 (d, 3H).

MS (ES/+): m/z=573 [MH-HCl]⁺.

EXAMPLE 44N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide-(diastereoisomer1)

TFA (0.44 mL) was added to a solution of intermediate 49a (23 mg) inanhydrous DCM (2 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wastreated at 0° C. with a 10% sodium hydroxide solution until pH=10. Theaqueous layer was extracted with DCM (3×8 mL). The combined organicextracts were dried, concentrated in vacuo and the residue was purifiedby flash chromatography (DCM/MeOH from 100:0 to 75:25) to give the titlecompound as a white foam (16 mg).

T.I.c.: DCM/MeOH 8:2, Rf=0.41 (detection with ninhydrine).

MS (ES/+): m/z=537 [M+H]⁺.

EXAMPLE 45N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride-(diastereoisomer 1)

The compound of Example 44 (16 mg) was dissolved in dry Et₂O (3 mL),cooled to 0° C. and treated with hydrochloric acid (1M in Et₂O—32 μL).The mixture was stirred at 0° C. for 1 hour, then Et2O was evaporatedunder Nitrogen flux and the residue was triturated in pentane (3×4 mL)and filtered to give the title compound (17 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.72 (b, 1H); 8.41 (b, 1H); 8.00 (s, 1H); 7.79(s, 2H); 7.34 (t, 1H); 7.01 (d, 1H); 7.00 (t, 1H); 5,65 (q, 1H); 3.72(m, 1H); 3.23 (bd. 1H); 3.15 (bd, 1H); 2.94 (m, 2H); 2.84 (m, 2H); 2.76(s, 3H); 2.35 (s, 3H); 2.16 (b, 1H); 1.81 (m, 2H); 1.62 (bd, 1H); 1.30(d, 3H).

MS (ES/+): m/z=537 [MH-HCl]⁺.

EXAMPLE 46N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide-(diastereoisomer2)

TFA (0.66 mL) was added to a solution of intermediate 49b (34 mg) inanhydrous DCM (2.5 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wastreated at 0° C. with a 10% sodium hydroxide solution until pH=10. Theaqueous layer was extracted with DCM (3×8 mL). The combined organicextracts were dried, concentrated in vacuo and the residue was purifiedby flash chromatography (DCM/MeOH from 100:0 to 75:25) to give the titlecompound as a colourless oil (22 mg).

T.I.c.: DCM/MeOH 9:1, containing 1.5% of conc. NH₄OH, Rf=0.43 (detectionwith ninhydrine).

MS (ES/+): m/z=537 [M+H]⁺.

EXAMPLE 47N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride-diastereoisomer 2)

The compound of Example 46 (22 mg) was dissolved in dry Et₂O (3 mL),cooled to 0° C. and treated with hydrochloric acid (1M in Et₂O—32 μL).The mixture was stirred at 0° C. for 1 hour, then Et₂O was evaporatedunder Nitrogen flux and the residue was triturated in pentane (3×4 mL)and filtered to give the title compound (28 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.48 (b, 2H); 7.93 (s, 1H); 7.49 (s, 2H); 7.33(t, 1H); 6.93 (d, 1H); 6.89 (t, 1H); 5,73 (q, 1H); 3.71 (m, 1H); 3.24(bd, 1H); 3.15 (bd, 1H); 2.93-2.91 (m, 2H); 2.84-2.81 (m, 2H); 2.72 (s,3H); 2.35 (s, 3H); 2.16 (b, 1H); 1.82 (m, 2H); 1.64 (bd, 1H); 1.45 (d,3H).

MS (ES/+): m/z=537 [MH-HCl]⁺.

EXAMPLE 48N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide

TFA (0.72 mL) was added to a solution of intermediate 50 (38 mg) inanhydrous DCM (3 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wastreated at 0° C. with a 10% sodium hydroxide solution until pH=10. Theaqueous layer was extracted with DCM (2×10 mL). The combined organicextracts were dried, concentrated in vacuo and the residue was purifiedby flash chromatography (DCM/MeOH from 100:0 to 75:25) to give the titlecompound as a colourless oil (25 mg).

T.I.c.: DCM/MeOH 8:2, Rf=0.32 (detection with ninhydrine).

MS (ES/+): m/z=545 [M+H]⁺.

EXAMPLE 49N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride

The compound of Example 48 (25 mg) was dissolved in dry Et2O (3 mL) andtreated at 0° C. with hydrochloric acid (1M in Et₂O—50 μL).

The mixture was stirred at 0° C. for 1 hour, then Et2O was evaporatedunder Nitrogen flux and the residue was triturated in pentane (3×4 mL)and filtered to give the title compound (33 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.57 (b, 2H); 7.66 (s, 1H); 7.35 (t, 1H); 7.14(s, 2H); 7.01 (d, 1H); 6.98 (t, 1H); 4.51 (d, 1H); 4.21 (d, 1H); 3.70(dm, 1H); 3.25 (bd, 1H); 3.16 (bd, 1H); 2.93-2.84 (m, 4H); 2.67 (s, 3H);2.36 (s, 3H); 2.18 (b, 1H); 1.82 (m, 2H); 1.61 (bd, 1H).

MS (ES/+): m/z=545 [MH-HCl]⁺.

EXAMPLE 50N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (50a) (enantiomer 1) andN-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (50b) (enantiomer 2)

The compound of example 49 (22 mg) was suspended in AcOEt (10 ml) andwashed with a 0.5M sodium hydroxide solution (10 mL); the organic phasewas dried, concentrated in vacuo to give a colourless oil which wasseparated into the enantiomers via HPLC (column: Chiracel OD 25 cm×20mm; mobile phase: n-hexane/2-Propanol 75:25; flow rate=6 mL/min; λ=225nm).

Thus, example 50a (6 mg) and example 50b (8.5 mg) were obtained.

EXAMPLE 50a

Chiral HPLC: Column Chiracel OD 25 cm×4.6 mm; mobile phase:n-hexane/2-Propanol 80:20; flow rate=1 mL/min; λ=225 nm, retention time12, 4 minutes, ratio 50a/50b=100/0

MS (ES/+): m/z=545 [M+H]⁺.

EXAMPLE 50b

Chiral HPLC: Column Chiracel OD 25 cm×4.6 mm; mobile phase:n-hexane/2-Propanol 80:20; flow rate=1 mL/min; λ=225 nm, retention time15,4 minutes, ratio 50a/50b=0/100

MS (ES/+): m/z=545 [M+H]⁺.

EXAMPLE 51N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (enantiomer 1)

The compound of Example 50a (6 mg) was dissolved in dry Et2O (2 mL) andtreated at 0° C. with hydrochloric acid (1M in Et₂O—12 μL).

The mixture was stirred at 0° C. for 15 minutes, then Et2O wasevaporated under Nitrogen flux and the residue was triturated in pentane(3×2 mL) to give the title compound (6 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.57 (b, 2H); 7.66 (s, 1H); 7.35 (t, 1H); 7.14(s, 2H); 7.01 (d, 1H); 6.98 (t, 1H); 4.51 (d, 1H); 4.21 (d, 1H); 3.70(m, 1H); 3.25 (bd, 1H); 3.16 (bd, 1H); 2.93-2.84 (m, 4H); 2.67 (s, 3H);2.36 (s, 3H); 2.18 (b, 1H); 1.82 (m, 2H); 1.61 (bd, 1H).

MS (ES/+): m/z=545 [MH-HCl]⁺.

EXAMPLE 52N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (enantiomer 2)

(The compound of Example 50b (8.5 mg) was dissolved in dry Et2O (2 mL)and treated at 0° C. with hydrochloric acid (1M in Et₂O—17 μL).

The mixture was stirred at 0° C. for 15 minutes, then Et2O wasevaporated under Nitrogen flux and the residue was triturated in pentane(3×2 mL) to give the title compound (6.5 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.57 (b, 2H); 7.66 (s, 1H); 7.35 (t, 1H); 7.14(s, 2H); 7.01 (d, 1H); 6.98 (t, 1H); 4.51 (d, 1H); 4.21 (d, 1H); 3.70(m, 1H); 3.25 (bd, 1H); 3.16 (bd, 1H); 2.93-2.84 (m, 4H); 2.67 (s, 3H);2.36 (s, 3H); 2.18 (b, 1H); 1.82 (m, 2H); 1.61 (bd, 1H).

MS (ES/+): m/z=545 [MH-HCl]⁺.

EXAMPLE 53N-[(3,5-dibromophenyl)methyl]-3-3,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(53a) (enantiomer 1)N-[(3,5-dibromophenyl)methyl]-3-(3,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(53b) (enantiomer 2)

TFA (2.5 mL) was added to a solution of intermediate 56 (135 mg) inanhydrous DCM (10 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hour, then it wastreated at 0° C. with a 10% sodium hydroxide solution until pH=10. Theaqueous layer was extracted with DCM (2×10 mL). The combined organicextracts were dried, concentrated in vacuo to give a racemate.

The mixture was separated into the enantiomers via HPLC (column:Chiracel OD 25 cm×20 mm; mobile phase: n-Hexane/2-Propanol 65:35; flowrate=6 mL/min; λ=225 nm). Thus, example 53a (37 mg) and example 53b (38mg) were obtained as white foams.

EXAMPLE 53a

Chiral HPLC: Column Chiralcel 25 cm×4.6 mm; mobile phase:n-Hexane/2-Propanol 70:30; flow rate=1 mL/min; λ=225 nm, retention time10.7 minutes; ratio 53a/53b=100/0

EXAMPLE 53b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm; mobile phase:n-Hexane/2-Propanol 70:30; flow rate=1 mL/min; λ=225 nm, retention time13.7 minutes; ratio 53a/53b=0/100 NMR (d₆-DMSO): δ (ppm) 7.68 (m, 1H);7.55 (m, 2H); 7.5-7.1 (m, 3H); 4.51-4.27 (dd, 2H); 3.5-2.5 (m, 7H); 3.00(s, 3H); 2.3-1.9 (bs, 1H); 1.9-1.3 (m, 4H).

MS (ES/+): m/z=581 [M+H]⁺.

EXAMPLE 54N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(54a)(enantiomer 1) andN-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(54b)(enantiomer 2)

TFA (4 mL) was added to a solution of intermediate 57 (440 mg) inanhydrous DCM (16 mL) previously cooled to −10° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 18 hours,then the solution was concentrated in vacuo. The residue was dilutedwith AcOEt (20 mL) and washed with a saturated potassium carbonatesolution (3×20 mL) and brine (20 mL). The organic phase was dried andconcentrated in vacuo to give a yellow oil which was submitted to HPLCseparation (Column: Chiralcel OD 25 cm×20 mm; mobile phase:n-hexane/i-PrOH 75:25; flow rate=7 mL/min; λ=225 nm). Thus, the titlecompounds example 54a (134 mg) and example 54b (131 mg) were obtained asa colourless oils.

EXAMPLE 54a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5 μm, mobile phasen-hexane/i-PrOH 80:20, flow rate=1 mL/min, λ=225 nm, retention time:12.6 minutes, ratio 54a/54b=100/0.

MS (ES/+): m/z=509 [MH]⁺.

EXAMPLE 54b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5 μm, mobile phasen-hexane/i-PrOH 80:20, flow rate=1 mL/min, λ=225 nm, retention time:15.9 minutes, ratio 54a/54b=0/100

MS (ES/+): m/z=509 [MH]⁺.

EXAMPLE 55N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (enantiomer 1)

The compound of example 54a (134 mg) was dissolved in Et2O (1 mL),previously cooled to −10° C. under a Nitrogen atmosphere, and treatedwith hydrochloric acid (1M in Et2O—309 μL). The mixture was stirred at0° C. for 10 minutes, then the solvent was decanted and the residue wastriturated with pentane (2×1 mL) to give the title compound (114.7 mg)as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.65 (b, 2H) 7.90 (s, 1H); 7.64 (s, 2H); 7.29(dd, 2H); 7.03 (t, 2H); 4.65 (d, 1H); 4.39 (d, 1H), 3.47 (m, 1H), 3.14(bt, 2H), 3.01 (dd, 1H), 2.97 (s, 3H), 2.95-2.75 (m, 2H), 2.83 (dd, 1H),2.05 (m, 1H), 1.8-1.55 (m. 3H).

MS (ES/+): m/z=509 [MH-HCl]⁺.

EXAMPLE 56N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (enantiomer 2)

The compound of example 54b (131 mg) was dissolved in Et2O (1 mL),previously cooled to −10° C. under a Nitrogen atmosphere, and treatedwith hydrochloric acid (1M in Et2O—308 μL). The mixture was stirred at0° C. for 10 minutes, then the solvent was decanted and the residue wastriturated with pentane (2×1 mL) to give the title compound (118.5 mg)as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.45 (b, 2H) 7.90 (s, 1H); 7.64 (s, 2H); 7.29(dd, 2H); 7.03 (t, 2H); 4.65 (d, 1H); 4.39 (d, 1H), 3.47 (m, 1H), 3.14(bt, 2H), 3.01 (dd, 1H), 2.97 (s, 3H), 2.95-2.75 (m, 2H), 2.83 (dd, 1H),2.05 (m, 1H), 1.8-1.55 (m, 3H).

MS (ES/+): m/z=509 [MH-HCl]⁺.

EXAMPLE 573-(4-chlorophenyl-N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(57a) (enantiomer 1) and3-(4-chlorophenyl)-N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(57b) (enantiomer 2)

TFA (1 mL) was added to a solution of intermediate 64 (115 mg) inanhydrous DCM (4 mL) previously cooled to −10° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 18 hours,then the solution was concentrated in vacuo. The residue was dilutedwith AcOEt (20 mL) and washed with a saturated potassium carbonatesolution (3×20 mL) and brine (20 mL). The organic phase was dried andconcentrated in vacuo to give a colourless oil which was submitted toHPLC separation (Column: Chiralcel OD 25 cm×20 mm; mobile phase:n-hexane/ethanol 70:30; flow rate=6.5 mL/min; λ=225 nm). Thus, the titlecompounds example 57a (41 mg) and example 57b (40 mg) were obtained as acolourless oils.

EXAMPLE 57a

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5 μm, mobile phasen-hexane/ethanol 70:30, flow rate=1 mL/min, λ=225 nm, retention time:6.69 minutes, ratio 57a/57b=100/0.

MS (ES/+): m/z=547 [MH]⁺.

EXAMPLE 57b

Chiral HPLC: Column Chiralcel OD 25 cm×4.6 mm×5 μm, mobile phasen-hexane/ethanol 70:30, flow rate=1 mL/min, λ=225 nm, retention time:10.85 minutes, ratio 57a/57b=0/100

MS (ES/+): m/z=547 [MH]⁺.

EXAMPLE 583-(4-chlorophenyl)-N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (58) (enantiomer 1)

The compound of example 57a (41 mg) was dissolved in Et2O (1 mL),previously cooled to 0° C. under a Nitrogen atmosphere, and treated withhydrochloric acid (1M in Et2O—83 μL). The mixture was stirred at 0° C.for 10 minutes, then the solvent was decanted and the residue wastriturated with pentane (2×1 mL) to give the title compound (37 mg) as awhite solid.

NMR (d₆-DMSO, 60° C.): δ (ppm) 8.8-8.3 (b, 2H) 7.7 (m, 3H); 7.1 (m, 4H);4.7-4.1 (dd, 2H); 3.5 (m, 1H); 3.3-2.8 (m, 4H); 2.9 (m, 2H), 2.9 (s,3H), 2.0-1.5 (m, 4H).

EXAMPLE 593-(4-chlorophenyl)-N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamidehydrochloride (59) (enantiomer 2)

The compound of example 57b (40 mg) was dissolved in Et2O (1 mL),previously cooled to −10° C. under a Nitrogen atmosphere, and treatedwith hydrochloric acid (1M in Et2O—80 μL). The mixture was stirred at 0°C. for 10 minutes, then the solvent was decanted and the residue wastriturated with pentane (2×1 mL) to give the title compound (40 mg) as awhite solid.

NMR (d₆-DMSO, 60° C.): δ (ppm) 8.8-8.3 (b, 2H) 7.7 (m, 3H); 7.1 (m, 4H);4.7-4.1 (dd, 2H); 3.5 (m, 1H); 3.3-2.8 (m, 4H); 2.9 (m, 2H), 2.9 (s,3H), 2.0-1.5 (m, 4H).

EXAMPLE 60N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinylidene)propionamide(isomer 1)

TFA (0.121 mL) was added to a solution of intermediate 73a (6 mg) inanhydrous DCM (0.6 mL) previously cooled to 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 1 hour, thenthe solution was concentrated in vacuo. The residue was diluted with DCMand washed with a saturated potassium carbonate solution. The aqueouslayer was extracted with further DCM (2×2 mL). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (DCM/MeOH from 95:5 to 9:1) to give thetitle compound (3 mg) as a white foam.

MS (ES/+): m/z=489 [M+H]⁺.

EXAMPLE 61N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinylidene)propionamide(isomer 2)

TFA (0.243 mL) was added to a solution of intermediate 73b (12 mg) inanhydrous DCM (1.2 mL) previously cooled to 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 1 hour, thenthe solution was concentrated in vacuo. The residue was diluted with DCMand washed with a saturated potassium carbonate solution. The aqueouslayer was extracted with further DCM (2×2 mL). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (DCM/MeOH from 95:5 to 9:1) to give thetitle compound (4.8 mg) as a white foam.

MS (ES/+): m/z=489 [M+H]⁺.

EXAMPLE 62(3E)-N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinylidene)propionamide

TFA (1.0 mL) was added to a solution of intermediate 81a (23 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluited with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 7/3) to give the title compound (0.015 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.2.

MS (ES/+): m/z=475 [M+H]⁺.

NMR (d₆-DMSO): δ (ppm) 7.98 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 2H); 7.08(t, 2H); 4.58 (s, 2H); 3.75 (s, 2H); 3.07 (t, 2H); 2.96 (s, 3H); 2.56(s, 2H); 2.40 (t, 2H).

EXAMPLE 63(3Z)-N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinylidene)propionamide

TFA (1.0 mL) was added to a solution of intermediate 81b (25 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluited with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 7/3) to give the title compound (0.013 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.22.

MS (ES/+): m/z=475 [M+H]⁺.

NMR (d₆-DMSO): δ (ppm) 7.98 (s, 1H); 7.77 (s, 2H); 7.24 (dd, 2H); 7.10(t, 2H); 4.6 (s, 2H); 3.61 (bs, 4H); 3.22 (t, 2H); 2.99 (s, 3H); 2.60(t, 2H).

EXAMPLE 64N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamide

A solution of TFA (1 mL) in anhydrous DCM (2 mL) was added to a solutionof intermediate 84 (40 mg) in anhydrous DCM (2 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The resulting solution was left infreezer overnight, then the solution was concentrated in vacuo. Theresidue was diluted with AcOEt/water and washed with a saturatedpotassium carbonate solution. The aqueous layer was extracted withfurther AcOEt. The combined organic extracts were dried and concentratedin vacuo to a residue which was purified by silica cartridge (fromDCM/MeOH 95:5 to 7:3) to give the title compound (15 mg) as a whitefoam.

MS (ES/+): m/z=503 [M+H]⁺.

EXAMPLE 65N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamidehydrochloride

Hydrochloric acid (1M in Et2O—50 μL) was added to a solution of example64 (12 mg) in anhydrous Et2O (0.3 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 15minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (3×1 mL) to give the title compound (12 mg) as white solid.

MS (ES/+): m/z=503 [MH-HCl]⁺.

NMR (d₆-DMSO): δ (ppm) 7.75 (s, 1H); 7.65 (s, 2H); 7.05 (dd, 2H); 6.95(dd, 2H); 6.00 (q, 1H); 3.40 (d, 2H); 2.95 (t, 2H); 2.80 (t, 2H); 2.50(s, 3H); 2.35 (t, 2H); 2.05 (t, 2H); 1.40 (d, 3H).

EXAMPLE 66N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamide

A solution of TFA (1 mL) in anhydrous DCM (2 mL) was added to a solutionof intermediate 85 (40 mg) in anhydrous DCM (2 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The resulting solution was left infreezer overnight, then the solution was concentrated in vacuo. Theresidue was diluted with AcOEt/water and washed with a saturatedpotassium carbonate solution. The aqueous layer was extracted withfurther AcOEt. The combined organic extracts were dried and concentratedin vacuo to a residue which was purified by silica cartridge (fromDCM/MeOH 95:5 to 7:3) to give the title compound (36 mg) as a whitefoam.

MS (ES/+): m/z=503 [M+H]⁺.

NMR (d₆-DMSO): δ (ppm) 7.75 (s, 1H); 7.65 (s, 2H); 7.05 (dd, 2H); 6.95(dd, 2H); 6.00 (q, 1H); 3.40 (d, 2H); 2.95 (t, 2H); 2.80 (t, 2H); 2.50(s, 3H); 2.35 (t, 2H); 2.05 (m, 2H); 1.40 (d, 3H).

EXAMPLE 67N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamidehydrochloride

Hydrochloric acid (1M in Et2O—50 μL) was added to a solution of example66 (15 mg) in anhydrous Et2O (0.2 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 15minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (3×1 mL) to give the title compound (13 mg) as white solid.

MS (ES/+): m/z=503 [MH-HCl]⁺.

EXAMPLE 68N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamide

A solution of TFA (1 mL) in anhydrous DCM (2 mL) was added to a solutionof intermediate 86 (42 mg) in anhydrous DCM (3 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The resulting solution was stirresat 0° C. overnight, then the solution was concentrated in vacuo. Theresidue was diluted with AcOEt/water and washed with a saturatedpotassium carbonate solution. The aqueous layer was extracted withfurther AcOEt. The combined organic extracts were dried and concentratedin vacuo to a residue which was purified by silica cartridge (DCM,DCM/MeOH from 95:5 to 7:3) to give the title compound (16.2 mg) as acolourless oil.

T.I.c.: CH/AcOEt 1:1, Rf=0.6 (detection with ninhydrine)

MS (ES/+): m/z=511 [M+H]⁺.

EXAMPLE 69N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamidehydrochloride

Hydrochloric acid (1M in Et2O—40 μL) was added to a solution of example68 (16 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then it was concentrated in vacuo. The residue was triturated withpentane (3×1 mL) to give the title compound (13.9 mg) as whitish solid.

NMR (CDCl3): δ (ppm) 9.72 (b, 2H); 7.58 (s, 1H); 7.21 (s, 1H); 7.04 (m,1H); 7.04 (m, 4H); 4.46 (s, 2H); 3.36 (b, 4H); 3.15 (s, 2H); 2.79 (s,3H); 2.8 (d, 2H); 2.49 (d, 2H).

MS (ES/+): m/z=509 [MH-HCl]⁺.

EXAMPLE 70N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide

TFA (1 mL) was diluted in DCM (3 ml) and added to a solution ofintermediate 90 (44 mg) in anhydrous DCM (1 mL) previously cooled to−10C under a Nitrogen atmosphere. The solution was left in freezerovernight, then it was concentrated in vacuo. The residue was dissolvedin AcOEt/H2O (10 mL/2 ml) and washed with saturated potassium carbonatesolution (10 mL). The organic layer was dried, concentrated in vacuo andthe residue was purified by silica cartridge (from DCM to DCM/MeOH80:20) to give the title compound (25.5 mg) as a white solid.

T.I.c.: DCM/MeOH 8:2, Rf=0.42 (detection with ninhydrine).

MS (ES/+): m/z=503 [M+H]⁺.

EXAMPLE 71N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide(diastereoisomer 1)

TFA (1 mL) was diluted in DCM (2 ml) and added to a solution ofintermediate 91a (25.5 mg) in anhydrous DCM (2 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The solution was left in freezerovernight, then it was concentrated in vacuo. The residue was dissolvedin AcOEt/H2O (10 mL/2 ml) and washed with saturated potassium carbonatesolution (10 mL). The organic layer was dried, concentrated in vacuo andthe residue was purified by silica cartridge (DCM, DCM/MeOH from 95:5 to80:20) to give the title compound (15 mg) as a white solid.

T.I.c.: DCM/MeOH 9:1 containing 1% NH4OH, Rf=0.58 (detection withninhydrine).

MS (ES/+): m/z=517[M+H]⁺.

EXAMPLE 72N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamidehydrochloride (diastereoisomer 1)

Hydrochloric acid (1M in Et2O—50 μL) was added to a solution of example71 (15 mg) in anhydrous Et2O (0.2 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 15minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (3×1 mL) to give the title compound (8.1 mg) as whitesolid.

NMR (d₆-DMSO): δ (ppm) 8.62 (b, 2H); 7.97 (s, 1H); 7.76 (s, 2H); 7.17(dd, 1H); 6.95 (td, 1H); 6.69 (dd, 1H); 5.71 (q, 1H); 5.45 (bs, 1H);3.99 (t, 1H); 3.46 (bs, 2H); 3.05/3.01 (bm, 2H); 2.83 (dd, 1H); 2.72(dd, 1H). 2.71 (s, 3H). 2.28 (s, 3H). 2.02 (bm, 2H). 1.36 (d, 3H).

EXAMPLE 73N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide(diastereoisomer 2)

TFA (1 mL) was diluted in DCM (2 ml) and added to a solution ofintermediate 91b (25.5 mg) in anhydrous DCM (2 mL) previously cooled to−10° C. under a Nitrogen atmosphere. The solution was left in freezerovernight, then it was concentrated in vacuo. The residue was dissolvedin AcOEt/H2O (10 mL/2 ml) and washed with saturated potassium carbonatesolution (10 mL). The organic layer was dried, concentrated in vacuo andthe residue was purified by silica cartridge (DCM, DCM/MeOH from 95:5 to80:20) to give the title compound (10 mg) as a white solid.

T.I.c.: DCM/MeOH 9:1 containing 1% NH4OH, Rf=0.48 (detection withninhydrine).

MS (ES/+): m/z=517 [M+H]⁺.

EXAMPLE 74N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamidehydrochloride (diastereoisomer 2)

Hydrochloric acid (1M in Et2O—50 μL) was added to a solution of example73 (10 mg) in anhydrous Et2O (0.2 mL) previously cooled to −10° C. undera Nitrogen atmosphere. The mixture was stirred at −10° C. for 15minutes, then it was concentrated in vacuo. The residue was trituratedwith pentane (4×1 mL) to give the title compound (10 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 8.81 (b, 2H); 7.93 (s, ₁H); 7.60 (s, 2H); 7.16(dd, 1H); 6.88 (dd, 1H); 6.82 (td, 1H); 5.74 (q, 1H); 5.42 (bs, 1H);3.99 (t, 1H); 3.48 (bs, 2H); 3.01 (m, 2H); 3.01 (dd, 1H); 2.69 (dd, 1H).2.71 (s, 3H). 2.25 (s, 3H). 2.05 (bm, 2H). 1.43 (d, 3H).

EXAMPLE 75N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinyl)propionamide(diastereoisomer A)

TFA (1.0 mL) was added to a solution of intermediate 94a (20 mg) inanhydrous DCM (4 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 2 hours, then it wasconcentrated in vacuo at 0° C. The residue was taken up with a saturatedsolution of potassium carbonate (10 mL) and diluited with EtOAc (50 mL).The organic phase was separated and the aqueous layer was extracted withEtOAc (2×50 mL). The collected organic phases were dried, concentratedin vacuo and the residue was purified by flash chromatography (DCM/MeOHfrom 9/1 to 6/4) to give the title compound (0.012 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 7.91 (s, 1H); 7.64 (s, 2H); 7.19 (dd, 2H); 6.92(dd, 2H); 4.62 (dd, 1H); 4.34 (dd, 1H); 2.97 (dd, 1H); 2.96 (dd, 1H);2.86 (dd, 1H); 2.83 (s, 3H); 2.62 (m, 1H); 2.59 (dd, 1H); 2.57 (m, 1H);2.42 (m, 1H); 2.18 (m, 1H), 1.29 (m, 1H); 1.02 (m, 1H).

MS (ES/+): m/z=477 [M+H]⁺.

EXAMPLE 76N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinyl)propionamide(diastereoisomer B)

TFA (1.0 mL) was added to a solution of intermediate 94b diastereoisomer2 (20 mg) in anhydrous DCM (4 mL) previously cooled at 0° C., under aNitrogen atmosphere. The solution was stirred at 0° C. for 2 hours, thenit was concentrated in vacuo at 0° C. The residue was taken up with asaturated solution of potassium carbonate (10 mL) and diluited withEtOAc (50 mL). The organic phase was separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The collected organic phases were dried,concentrated in vacuo and the residue was purified by flashchromatography (DCM/MeOH from 9/1 to 6/4) to give the title compound(0.011 g) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.12.

NMR (d₆-DMSO): δ (ppm) 7.91 (s, 1H); 7.65 (s, 2H); 7.19 (dd, 2H); 6.92(dd, 2H); 4.61 (dd, 1H); 4.36 (dd, 1H); 2.87 (dd, 1H); 2.96 (dd, 1H);2.86 (dd, 1H); 2.84 (s, 3H); 2.75 (m, 1H); 2.71 (m, 1H); 2.68 (dd, 1H);2.32 (m, 1H); 2.17 (m, 1H); 1.85 (m, 1H); 1.29 (m, 1H).

MS (ES/+): m/z=477 [M+H]⁺.

EXAMPLE 77N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide(diastereoisomer A)

TFA (0.365 mL) was added to a solution of intermediate 97a (18 mg) inanhydrous DCM (1.8 mL) previously cooled to 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 1 hour, thenthe solution was concentrated in vacuo. The residue was diluted with DCMand washed with a saturated potassium carbonate solution. The aqueouslayer was extracted with further DCM (2×2 mL). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (DCM/MeOH 95:5 to 9:1) to give thetitle compound (7.8 mg) as a white foam.

T.I.c.: DCM/MeOH 8:2, Rf=0.64.

MS (ES/+): m/z=509 [M+H]⁺.

EXAMPLE 78N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer A)

Hydrochloric acid (1M in Et2O—11 μL) was added to a solution of example77 (7.8 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. undera Nitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (3×0.3 mL) to give the title compound (5 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 9.0-8.0 (b, 2H); 7.94 (s, 1H); 7.66 (s, 2H); 7.31(m, 2H); 7.07 (t, 2H); 4.7-4.3 (dd, 2H); 3.55 (m, 2H); 3.2-2.8 (m, 5H);3.00 (s, 3H); 2.5-1.7 (m, 4H).

MS (ES/+): m/z=509 [M+H-HCl]⁺.

EXAMPLE 79N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide(diastereoisomer B)

TFA (0.750 mL) was added to a solution of intermediate 97b (37 mg) inanhydrous DCM (3.7 mL) previously cooled to 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 1 hour, thenthe solution was concentrated in vacuo. The residue was diluted with DCMand washed with a saturated potassium carbonate solution. The aqueouslayer was extracted with further DCM (2×4 mL). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (DCM/MeOH 95:5 to 9:1) to give thetitle compound (20 mg) as a colourless oil.

T.I.c.: DCM/MeOH 8:2, Rf=0.56.

NMR (CDCl3): δ (ppm) 7.79 (s, 1H); 7.54 (s, 2H); 7.27 (m, 2H); 6.99 (t,2H); 4.61 (q, 2H); 3.5 (m, 1H); 3.0-2.4 (m, 9H); 1.8-1.2 (m, 4H).

EXAMPLE 80N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamidehydrochloride (diastereoisomer B)

Hydrochloric acid (1M in Et2O—9 μL) was added to a solution of example79 (4 mg) in anhydrous Et20 (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 15 minutes,then the liquid phase was removed. The residue was triturated withpentane (3×0.3 mL) to give the title compound (4 mg) as a white solid.

MS (ES/+): m/z=509 [M+H-HCl]⁺.

EXAMPLE 81N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide(diastereoisomer1)

TFA (1 mL) was added to a solution of intermediate 104a (31 mg) in DCM(4 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 3 hours, then the solution was diluted with further DCM andwashed with a saturated potassium carbonate solution. The combinedorganic extracts were dried, concentrated in vacuo and the residue waspurified by flash chromatography (from DCM to DCM/MeOH 80:20) to givethe title compound (7 mg) as a pale yellow oil.

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 82N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamidehydrochloride(diastereoisomer 1)

Hydrochloric acid (1M in Et2O—11 μL) was added to a solution of example81 (7 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) to give the title compound (3.5 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.86 (bs, 2H), 7.98 (s, 1H), 7.76 (s, 2H), 7.27(m, 2H), 7.07 (t, 2H), 5.72 (m, 1H), 3.93 (m, 2H), 3.57 (t, 1H), 3.36(m, 1H), 3.19 (d, 1H), 3.05 (d, 1H), 2.90 (m, 1H), 2.75 (m, 2H), 2.71(s, 3H), 2.30 (bm, 1H), 1.38 (d, 3H).

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 83N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide(diastereoisomer 2)

TFA (1 mL) was added to a solution of intermediate 104b (20 mg) in DCM(4 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 3 hours, then the solution was diluted with further DCM andwashed with a saturated potassium carbonate solution. The combinedorganic extracts were dried, concentrated in vacuo and the residue waspurified by flash chromatography (from DCM to DCM/MeOH 80:20) to givethe title compound (15 mg) as a pale yellow oil.

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 84N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamidehydrochloride(diastereoisomer 2)

Hydrochloric acid (1M in Et2O—32 μL) was added to a solution of example83 (15 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) to give the title compound (7 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.66 (bs, 2H), 7.93 (s, 1H), 7.61 (s, 2H), 7.26(m, 2H), 7.02 (t, 2H), 5.76 (m, 1H), 3.93 (m, 1H), 3.84 (m, 1H), 3.58(t, 1H), 3.38 (m, 1H), 3.18 (d, 1H), 3.04 (d, 1H), 2.90-2.70 (m, 3H),2.70 (s, 3H), 2.35 (t, 1H), 1.46 (d, 3H).

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 85N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide(diastereoisomer 3)

TFA (0.5 mL) was added to a solution of intermediate 105a (16 mg) in DCM(2 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 3 hours, then the solution was diluted with further DCM andwashed with a saturated potassium carbonate solution. The combinedorganic extracts were dried, concentrated in vacuo and the residue waspurified by flash chromatography (from DCM to DCM/MeOH 80:20) to givethe title compound (8.5 mg) as a pale yellow oil.

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 86N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamidehydrochloride(diastereoisomer 3)

Hydrochloric acid (1M in Et2O—18 μL) was added to a solution of example85 (8.5 mg) In anhydrous Et2O (0.5 mL) previously cooled to 0° C. undera Nitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) to give the title compound (7.5 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.81 (bs, 2H), 7.96 (s, 1H), 7.74 (s, 2H), 7.29(m, 2H), 7.09 (t, 2H), 5.65 (m, 1H), 3.91 (m, 1H), 3.77 (m, 1H), 3.64(t, 1H), 3.27 (m, 1H), 3.09 (d, 1H), 2.93 (d, 1H), 2.86 (m, 2H), 2.70(s, 3H), 2.80-2.60 (m, 2H), 1.30 (d, 3H).

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 87N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide(diastereoisomer 4)

TFA (0.5 mL) was added to a solution of intermediate 105b (19 mg) in DCM(2 mL) under a Nitrogen atmosphere. The resulting solution was stirredat r.t. for 3 hours, then the solution was diluted with further DCM andwashed with a saturated potassium carbonate solution. The combinedorganic extracts were dried, concentrated in vacuo and the residue waspurified by flash chromatography (from DCM to DCM/MeOH 80:20) to givethe title compound (11 mg) as a pale yellow oil.

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 88N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamidehydrochloride(diastereoisomer 4)

Hydrochloric acid (1M in Et2O—23 μL) was added to a solution of example87 (11 mg) in anhydrous Et2O (0.5 mL) previously cooled to 0° C. under aNitrogen atmosphere. The mixture was stirred at 0° C. for 30 minutes,then the liquid phase was removed. The residue was triturated withpentane (2×1 mL) to give the title compound (7.5 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.80 (bs, 2H), 7.91 (s, 1H), 7.50 (s, 2H), 7.27(m, 2H), 7.01 (t, 2H), 5.72 (m, 1H), 3.98 (M, 1H), 3.76 (m, 1H), 3.65(t, 1H), 3.27 (m, 1H), 3.10 (d, 1H), 3.00-2.80 (d, 3H), 2.68 (m, 2H),2.64 (s, 3H), 1.40 (d, 3H).

MS (ES/+): m/z=507 [M+H]⁺.

EXAMPLE 89N-{3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinyl)propionamide(diastereoisomer A)

TFA (0.375 mL) was added to a solution of intermediate 109a (15 mg) inanhydrous DCM (1.7 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hours, then it wasconcentrated in vacuo at 0° C. The residue was purified by SCX cartridge(load with DCM and elution with MeOH, NH3 0.25M in MeOH) to give thetitle compound as a colourless oil:

T.I.c.: AcOEt 100%, Rf=0.15.

NMR (CDCl3): δ (ppm) 7.76 (s, 1H); 7.52 (s, 2H); 7.12 (dd, 2H); 6.95 (t,2H); 4.67-4.45 (dd, 2H); 3.3-2.1 (m, 7H); 2.1-0.8 (m, 5H); 2.86 (s, 3H).

MS (ES/+): m/z=491 [M+H]⁺.

EXAMPLE 90N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinyl)propionamide(diastereoisomer B)

TFA (0.75 mL) was added to a solution of intermediate 109b (40 mg) inanhydrous DCM (3.7 mL) previously cooled at 0° C., under a Nitrogenatmosphere. The solution was stirred at 0° C. for 1 hours, then it wasconcentrated in vacuo at 0° C. The residue was purified by SCX cartridge(load with DCM and elution with MeOH, NH3 0.25M in MeOH) to give thetitle compound as a colourless oil:

T.I.c.: AcOEt 100%, Rf=0.15.

NMR (CDCl3): δ (ppm) 7.76 (s, 1H); 7.52 (s, 2H); 7.13 (dd, 2H); 6.93 (t,2H); 4.62-4.46 (dd, 2H); 3.1-2.1 (m, 7H); 2.1-1.1 (m, 5H); 2.85 (s, 3H).

MS (ES/+): m/z=491 [M+H]⁺.

EXAMPLE 91N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)propionamide

DIPEA (85 μL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (50.9 mg) were added to a solution of intermediate 112(30 mg) in anhydrous DMF (3.5 mL) under a Nitrogen atmosphere. Afterstirring for 10 minutes,{[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine hydrochloride (53.8mg) was added. The mixture was stirred at r.t. for 16 hours, then it wasdiluted with AcOEt, washed with a 5% sodium hydrogen carbonate solutionand brine. The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH, CH/AcOEt 1:1, thenAcOEt) to give the title compound (42 mg) as a white solid.

T.I.c.: AcOEt, Rf=0.13 (detection with ninhydrine).

NMR (d₆-DMSO): δ (ppm) 8.36 (d, 2H); 7.92 (s, 1H); 7.70 (s, 2H); 7.35(dd, 2H); 7.32 (d, 2H); 7.02 (dd, 2H); 4.58 (d, 1H); 4.53 (d, 1H); 4.51(dd, 1H); 3.28 (dd, 1H); 3.19 (dd, 1H); 3.02 (s, 3H).

MS (ES/+): m/z=485 [M+H]⁺.

Pharmacy Examples

A. Capsules/Tablets

-   -   Active ingredient 25.0 mg    -   PVP 2.5 mg    -   Microcrystalline Cellulose 198.5 mg    -   Croscarmellose Sodium 2.5 mg    -   Magnesium Stearate 1.5 mg

The active ingredient is blended with the other excipients. The blendcan be used to fill gelatin capsules or compressed to form tablets usingappropriate punches. The tablets can be coated using conventionaltechniques and coatings.

B. Tablets

-   -   Active ingredient 25.0 mg    -   Microcrystalline Cellulose 264.0 mg    -   Croscarmellose Sodium 10.0 mg    -   Magnesium Stearate 1.0 mg

The active ingredient is blended with microcrystalline cellulose andcroscarmellose sodium. Magnesium stearate is then added to the previousblend. The mixture thus obtained can be compressed using appropriatepunches and the tablets coated using conventional techniques andcoatings.

C) Infusion

-   Active ingredient 2-50 mg/ml-   Buffer solution pH 4.5 suitable for infusion qs to 100 ml-   (e.g. sodium citrate in NaCl 0.9% or 5% dextrose)

The formulation may be packed in glass vials or plastic bag.

The affinity of the compound of the invention for the NK₁ receptor wasdetermined using the NK₁ receptor binding affinity method measuring invitro by the compounds' ability to displace [3H]—substance P(SP) fromrecombinant human NK₁ receptors expressed in Chinese Hamster Ovary (CHO)cell membranes. The affinity values are expressed as negative logarithmof the inhibition constant (Ki) of displacer ligands (pKi).

The pKi values obtained as the average of at least two determinationswith representative compounds of the invention are within the range of10.44 to 7.54.

The inhibitory activity of the compound of the invention at the humanserotonin transporter was determined using the hSERT uptake affinitymethod and measuring the compounds' ability to inhibit uptake of [3H]5HT in hSERT-LLCPK cells. The data have been digitally processed toobtain the pIC50 values of the antagonists. The pIC50 values obtained asthe average of at least two determinations with representative compoundsof the invention are within the range of 7.19 to 6.24.

The inhibitory activity of the compound of the invention at the ratserotonin transporter was determined using the rSERT uptake affinitymethod and measuring the compounds' ability to inhibit uptake of [3H]5HT in rSERT-LLCPK cells. The data have been digitally processed toobtain the pIC50 values of the antagonists. The pIC50 values obtained asthe average of at least two determinations with representative compoundsof the invention are within the range of 7.38 to 3.97.

Particularly preferred compounds of the invention have shown a NK1receptor binding affinity (pki) greater than 8 and an inhibitoryactivity (pIC50) at the hSERT greater than 7.

1. A compound of formula (I)

wherein R is halogen, C₁₋₄ alkyl, cyano, C₁₋₄ alkoxy, trifluoromethyl ortrifluoromethoxy; R₁ is a 5 or 6 membered heteroaryl group, in which the5-membered heteroaryl group contains at least one heteroatom selectedfrom oxygen, sulphur or nitrogen and the 6-membered heteroaryl groupcontains from 1 to 3 nitrogen atoms, or R₁ is a 4, 5 or 6 memberedheterocyclic group, wherein said 5 or 6 membered heteroaryl or the 4, 5or 6 membered heterocyclic group may optionally be substituted by one tothree substituents, which may be the same or different, selected from(CH₂)_(p)R₆, wherein p is zero or an integer from 1 to 4 and R₆ isselected from: halogen, C₁₋₄alkoxy, C₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄alkyl optionally substituted by halogen, cyano or C₁₋₄ alkoxy, hydroxy,cyano, nitro, trifluoromethyl, carboxy, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂NH(C₃₋₇ cycloalkyl), N(C₁₋₄ alkyl)(C₃₋₇ cycloalkyl);NH(C₁₋₄alkylOC₁₋₄alkoxy), OC(O)NR₇R₈, NR₈C(O)R₇ or C(O)NR₇R₈; R₂ ishydrogen, or C₁₋₄ alkyl R₃ and R₄ independently are hydrogen, C₁₋₄ alkylor R₃ together with R₄ and the carbon to which they are bonded is C₃₋₇cycloalkyl; R₅ is trifluoromethyl, S(O)_(q)C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄alkoxy, trifluoromethoxy, halogen or cyano; R₇ and R₈ independently arehydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl; L is a single or a double bond;n is an integer from 1 to 3; m is zero or an integer from 1 to 3; q iszero or an integer from 1 to 2; provided that a) when L is a doublebond, R₁ is not an optionally substituted 5 or 6 membered heteroarylgroup, in which the 5-membered heteroaryl group contains at least oneheteroatom selected from oxygen, sulphur or nitrogen and the 6-memberedheteroaryl group contains from 1 to 3 nitrogen atoms; b) the group R₁ islinked to the carbon atom shown as * via a carbon atom; and c) when theheteroatom contained in the group R₁ is substituted, p is not zero; andpharmaceutically acceptable salts and solvates thereof.
 2. A compound asclaimed in claim 1 wherein R is halogen or C₁₋₄ alkyl and n is aninteger from 1 to
 2. 3. A compound as claimed in claim 1 wherein R₅ istrifluoromethyl, methyl, methoxy, bromine, chlorine or fluorine atom andm is an integer from 1 to
 2. 4. A compound as claimed in claim 1 whereinR₁ is piperidyl, morpholinyl, 1,2,3,6-tetrahydro-4-pyridinyl, pyridyl orpyrrolidinyl.
 5. A compound as claimed in claim 1 wherein R is halogenor C₁₋₄ alkyl and n is an integer from 1 to 2; R₁ is piperidyl,2-morpholinyl, 1,2,3,6-tetrahydro-4-pyridinyl, pyridyl or pyrrolidinyland wherein R₁ is optionally substituted by one or two groups selectedfrom halogen, C₁₋₄ alkyl or ethylC₁₋₄ alkoxy; R₂ and R₃ areindependently hydrogen or methyl; R₄ is hydrogen, methyl or togetherwith R₃ is cyclopropyl and R₅ is trifluoromethyl, methyl, methoxy,bromine, chlorine or fluorine atom and m is preferably an integer from 1to
 2. 6. A compound selected from:N-(3,5-Bis-trifluoromethyl-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-piperidin-4-yl-propionamide;N-[1-(3,5-Dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-N-methyl-3-[1-(2-methoxyethyl)-piperidin-4-yl]-propionamide;N-(3,5-Dichloro-benzyl)-3-(4-fluoro-phenyl)-3-(4-fluoro-piperidin-4-yl)-N-methyl-proprionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-{1-[2-(methyloxy)ethyl]-4-piperidinyl}propionamideN-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propanamide;N-{1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}-3-(4-fluorophenyl)-3-(4-piperidinyl)propionamide;N-{[3-bromo-4-(methyloxy)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;N-[(3,5-dimethylphenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;N-[(3,4-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;N-[(3-fluoro-2-methylphenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide;N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(2,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-2-methylphenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-[(3,5-dibromophenyl)methyl]-3-(3,4-dichlorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;3-(4-chlorophenyl)-N-[(3,5-dibromophenyl)methyl]-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinylidene)propionamide;N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinylidene)propionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide;N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)propionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-pyrrolidinyl)propionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide;N-{-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(2-morpholinyl)propionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(3-piperidinyl)propionamide;N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)propionamide;and enantiomers, diastereiosomers, pharmaceutically acceptable salts andsolvates thereof.
 7. A compound selected fromN-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide(diastereoisomer1);N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-N-methyl-3-(4-piperidinyl)propionamide(diastereoisomer 2);N-{(1R-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(diastereoisomer 1;N-[(3,5-dibromophenyl)methyl]-3-(4-fluorophenyl)-3-(4-fluoro-4-piperidinyl)-N-methylpropionamide(enantiomer 2);N{[3,5-bis(trifluoromethyl)phenyl]methyl}-3-(4-fluorophenyl)-3-(3-fluoro-3-piperidinyl)-N-methylpropionamide(diastereoisomer A); and pharmaceutically acceptable salts and solvatesthereof.
 8. A process for the preparation of a compound as claimed inclaim 1 which comprises reacting an activated derivative of thecarboxylic acid of formula (II) wherein R₁ has the meaning previouslydefined or is a protected group thereof, with amine (III)

wherein R₂ is C₁₋₄ alkyl or a nitrogen protecting group, followed wherenecessary by removal of any protecting group. 9-11. (canceled)
 12. Apharmaceutical composition comprising a compound as claimed in claim 1in admixture with one or more pharmaceutically acceptable carriers orexcipients.
 13. (canceled)
 14. A compound as claimed in claim 1 whereinR is fluorine or chlorine or methyl and n is an integer from 1 to
 2. 15.A compound as claimed in claim 1 wherein R is fluorine or chlorine ormethyl and n is an integer from 1 to 2; R₁ is piperidyl, 2-morpholinyl,1,2,3,6-tetrahydro-4-pyridinyl, pyridyl or pyrrolidinyl and wherein R₁is optionally substituted by one or two groups selected from fluorine,methyl or ethylC₁₋₄ alkoxy; R₂ and R₃ are independently hydrogen ormethyl; R₄ is hydrogen, methyl or together with R₃ is cyclopropyl and R₅is trifluoromethyl, methyl, methoxy, bromine, chlorine or fluorine atomand m is preferably an integer from 1 to
 2. 16. A method for thetreatment of a condition mediated by a tachykinin and/or selectiveinhibition of serotonin reuptake transporter protein in a mammal in needthereof, comprising administering an effective amount of a compound asclaimed in claim
 1. 17. The method as claimed in claim 16, wherein saidtachykinin is substance P.
 18. The method as claimed in claim 16,wherein said mammal is man.